Bicyclic benzenoid aminoalkylene ethers and thioethers, pharmaceutical compositions and use

ABSTRACT

A class of bicyclic benzenoid aminoalkylene ether and thioether compounds exhibiting pharmacological activity, including anti-secretory and anti-ulcerogenic activity, pharmaceutical compositions comprising these compounds, and methods for the treatment of gastrointestinal hyperacidity and ulcerogenic disorders in mammals using said compositions.

This application is a continuation-in-part of U.S. Application Ser. No.489,702, filed on Apr. 29, 1983, now U.S. Pat. No. 4,529,723.

FIELD OF THE INVENTION

This invention relates to a class of bicyclic benzenoid compoundscharacterized by an ether or thioether substituent on the phenyl ringand an exocyclic nitrogen substituent on the other ring of the bicyclicring system and methods for the treatment of physiological disorders,including gastrointestinal disorders in humans and other mammals.

REPORTED DEVELOPMENTS

Gastrointestinal hyperacid secretion, stomach and intestinal ulceration,and gastritis are major gastrointestinal disorders observed in thegeneral adult populations of industrialized societies. Many factors,including the production of excess gastric acid and the weakening of thelining of the stomach and gastrointestinal tract against such acid areimplicated as causes of these disorders. Traditional treatment of thesedisorders has involved the administration of antacids to neutralize theexcess gastric acid and the administration of antisecretory drugs whichgenerally reduce the production of all gastric secretions.

In the last few years, the treatment of gastrointestinal disorders suchas peptic ulcer has changed to include the use of anti-secretory drugswhich selectively block the production of gastric acid. These drugs arebelieved to interfere with the body's physiological pathway responsiblefor the production of gastric acid by blocking the action of histamine.Histamine production is induced in the body by a number of stimuli,including stress, allergic reaction, etc., and acts to increase gastricsecretion, dilate blood vessels and stimulate smooth muscle tissue.Histamine is believed to function by way of interaction with histaminereceptors in the body. The subdivision of these receptors into twogroups, the H₁ - and H₂ -receptors, was proposed by Ash and Schild(Brit. J. Pharmacol. Chemother, 1966, 27, 427) and Black et al (Nature1972, 236, 385). The H₁ -receptor is involved in the bronchial andgastrointestinal smooth muscle stimulative action of histamine. Drugswhich block this action are labelled "antihistamines" (e.g. mepyramine).

Black et al, cited above, described the group of substances which act athistamine receptors other than the H₁ -receptor as the H₂ -receptors.Blocking the action of histamine at the H₂ -receptors will selectivelyblock histamine's stimulative action on gastric acid secretion and heartrate. Burimamide was the first clinically effective H₂ -receptorantagonist inhibiting gastric secretion in man; but Burimamide's oralabsorptivity is poor. Subsequent studies developed the orally activeMetiamide, the side effects of which limited clinical use, andCimetidine which has been marketed as an anti-ulcer drug. A number ofclasses of heterocyclic chemical compounds have been reported as H₂-receptor antagonists, for example, those disclosed in U.S. Pat. Nos.4,104,381, 4,279,819, 4,323,566, 4,390,701, 4,395,553, and Britishpublished patent applications GB No. 2067987A and GB No. 2047238A, andEPO publication No. 0081955A2, the disclosures of which are incorporatedby reference.

Another method for the prevention or treatment of gastric ulcercomprises the use of drugs which neither neutralize nor inhibit thesecretion of gastric acid. These drugs constitute a class of anti-ulcercompounds which function to enhance the normal defense mechanisms of thebody, rather than to reduce normal body secretions, and are described as"cytoprotective" agents. It has been proposed that such agents act tostrengthen the mucosal lining of the gastrointestinal system by one ormore mechanisms, thereby preventing any damage which could result fromthe action of strong gastric acid. Prostaglandins have been implicatedin the mechanism of cytoprotection by a number of workers in the field.See, the discussion of cytoprotection in Robert, Andre, "Prostaglandinsand Digestive Diseases", Advances in Prostaglandin and ThromboxaneResearch, Vol. 8 (Raven Press, N.Y. 1980), and Robert et al,"Cytoprotection by Prostaglandins in Rats", Gastroenterology, 77,433-443 (1979), hereby incorporated by reference. Drugs, other thanprostaglandins, which exhibit cytoprotective activity includecarbenoxolone sodium, reported to exhibit undesirable side effects, suchas edema, diastolic hypertension or hypokalemia, and thethiazol-2-yl-carbamoylcarboxylic acids, esters and imides described inU.S. Pat. No. 4,321,372.

Compounds of the present invention comprise bicyclic benzenoids whichexhibit anti-secretory activity, H₂ -receptor antagonist activity,anti-ulcer activity and cytoprotective activity.

SUMMARY OF THE INVENTION

This invention comprises a class of compounds according to Formula I##STR1## wherein: a is 0, 1 or 2;

b is 0 or 1;

c is b, 1-b, 2-b or 3-b;

d is 0 or 1;

e is 2, 3 or 4;

X is oxygen, sulfur, ##STR2## Z is --NHR₄, ##STR3## R₁ is --NR₂ R₃,##STR4## R₂ and R₃ are each independently H or alkyl, or both togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedring which may include one to three additional hetero atoms of N, O orS;

R₄ is selected from the group consisting of H, ##STR5## R₅ is H or loweralkyl; R₆ is H or lower alkyl or R₆ together with R₂ are ethylene orpropylene and form a 5 or 6 membered ring with the nitrogen atoms towhich they are attached;

R₇ is hydrogen, lower alkyl, lower alkenyl, aryl, arloweralkyl,hydroxyloweralkyl, acyloxyloweralkyl, loweralkoxyloweralkyl,aryloxyalkyl, aroyloxyalkyl, aralkyloxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, alkoxy, alkylthio, halogenor NR₈ R₉, where:

R₈ is hydrogen, lower alkyl, lower alkenyl or arloweralkyl; and

R₉ is hydrogen, COR₁₀, SO₂ R₁₁ or ##STR6## R₁₀ is hydrogen, lower alkyl,aryl, arloweralkyl, loweralkoxy, heteroaryl, or monocyclicheteroarylalkyl;

R₁₁ is loweralkyl or aryl;

R₁₂ is hydrogen, lower alkyl, cycloloweralkyl, aryl or lower aralkyl;

R₁₃ is halo, amino, nitro, cyano, hydroxy, lower alkyl, lower alkoxy,lower alkanoyl, cycloloweralkyl, mono- or di lower alkyl amino, loweralkanoyl, lower alkanoyl amino, haloloweralkyl, aryl, mercapto,loweralkoxy carbonyl, carboxy, loweralkylthio, loweralkylsulfonyl,sulfamoyl, or lower alkyl sulfamoyl; and

R₁₄ is SO₂, SO, S or C═O;

or a pharmaceutically acceptable salt thereof.

Compounds within the scope of Formula I exhibit physiological activityin mammals including anti-secretory activity, histamine H₂ -receptorantagonist activity, anti-ulcer activity and cytoprotective activity.

Another aspect of this invention relates to the class of isomericcompounds according to Formula I, which class of compounds exhibits anunexpected and surprising level of physiological activity includinganti-secretory, histamine H₂ -receptor antagonist and anti-ulceractivity.

This invention also relates to methods for the treatment and preventionof gastrointestinal hyperacidity and ulcerogenic disorders in humans andother mammals comprising administering to a patient an effective amountof a compound within the description of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

Preferred classes of compounds according to this invention are describedby Formulae II, III, IV, V and VI. ##STR7## wherein: a is 0, 1 or 2;

c is 0, 1, 2 or 3;

d is 0 or 1;

e is 2, 3 or 4;

X is oxygen or sulfur;

Z is NHR₄ or ##STR8## R₁ is --NR₂ R₃ ; R₂, R₃, R₄ and R₅ are asdescribed above. ##STR9## wherein: a is 0, 1 or 2;

d is 0 or 1;

e is 2, 3 or 4;

X is oxygen or sulfur;

Z is NHR₄ or ##STR10## R₁ is --NR₂ R₃ ; R₂, R₃, R₄ and R₅ are asdescribed above. ##STR11## wherein: a is 1 or 2;

d is 0 or 1;

e is 2, 3 or 4;

X is oxygen or sulfur;

Z is NHR₄ or ##STR12## R₁ is --NR₂ R₃ ; R₂, R₃, R₄ and R₅ are asdescribed above.

A most preferred class of compounds within the scope of Formula Icomprises the compounds of Formula I wherein:

a is 0;

b is 0;

c is 0, 1, 2 or 3;

d is 0;

e is 3;

X is oxygen; and

Z is NHR₄ or ##STR13##

A preferred subclass of compounds is described by Formula IV or V,wherein:

a and d are 0;

e is 3; and

X is oxygen.

Another preferred subclass of compounds is described by Formula IV or V,wherein:

a is 0;

d is 1;

e is 2; and

X is sulfur.

A preferred Z substituent is selected from the group including ##STR14##

A most preferred class of compounds is described by Formula VII.##STR15## wherein: c is 1 or 2;

d is 0 or 1;

e is 2, 3 or 4;

X is oxygen or sulfur;

R₁ is --NR₂ R₃ ;

R₂ and R₃ together with the nitrogen to which they are attached form a5, 6 or 7 membered heterocyclic ring which may include one to threeadditional hetero atoms of N, O or S;

or a pharmaceutically acceptable salt thereof.

A particularly interesting class of compounds according to Formula VIIcomprises those compounds wherein R₁ is 1-piperidinyl, 1-pyrrolidinyl,1-morpholinyl or 1-azepinyl.

The compounds of Formulae I to VII may also form hydrates and exhibittautomerism. Formulae I to VII are intended to encompass all hydratesand tautomers, as well as any diastereomers and optical enantiomers.

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbonatoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl,isopropyl, butyl, sec-butyl, and tert-butyl.

"5, 6 or 7 membered heterocyclic ring" means a

nitrogen-containing ring of the formula ##STR16## where Y is alkylene oralkylidinyl having from one to six carbon atoms, and may include one tothree atoms of N, O or S. Exemplary heterocyclic groups includepiperidinyl, pyrrolidinyl, morpholinyl, azepinyl, pyrrolyl, imidazolyl,pyrazolyl, and thiamorpholinyl.

"Aroyl" means an acyl derivative of an aromatic carboxylic acid such asbenzoyl and quinolyl.

"Heteroaryl" means a five or six membered monocyclic ring or 9 or 10membered bicyclic ring either of which may contain one or moreheteroatoms of nitrogen, oxygen or sulfur, including furyl, pyridyl,thiazolyl, quinolinyl, indolyl or thienyl.

"Lower alkanoyl" means an acyl derivative of a lower alkanoic acid suchas acetyl and propionyl.

"Aryl" means an aromatic hydrocarbon radical group such as phenyl,toluyl, quinolyl, pyridyl, and includes phenyl, toluyl, quinolyl orpyridyl substituted by one or more substituent groups including loweralkyl, halo, carboxyl, amino, loweralkyl amino, amido, hydroxyl, nitro,cyano, or sulfonyl. Preferred aryl groups include phenyl and toluyl.

Representative examples of compounds of this invention are listed belowin Tables A, B, C, D, E, F, G and H.

                  TABLE A    ______________________________________    R.sub.1    Z    ______________________________________     ##STR17##    wherein substitution may be at the 5,6,7 or 8 position    ______________________________________    N(CH.sub.3).sub.2                ##STR18##     ##STR19##                ##STR20##     ##STR21##                ##STR22##    NH.sub.2                ##STR23##     ##STR24##                ##STR25##     ##STR26##                ##STR27##    ______________________________________     ##STR28##    ______________________________________     ##STR29##                ##STR30##    N(CH.sub.3).sub.2                ##STR31##    NHCH.sub.3                ##STR32##     ##STR33##                ##STR34##     ##STR35##                ##STR36##    N(CH.sub.3).sub.2                ##STR37##    N(CH.sub.3).sub.2                ##STR38##     ##STR39##                ##STR40##     ##STR41##                ##STR42##     ##STR43## CN     ##STR44##                ##STR45##     ##STR46## NH.sub.2     ##STR47##  CN     ##STR48##                ##STR49##     ##STR50## NH.sub.2     ##STR51##                ##STR52##     ##STR53##                ##STR54##     ##STR55##                ##STR56##     ##STR57##                ##STR58##     ##STR59##                ##STR60##     ##STR61##                ##STR62##     ##STR63##                ##STR64##    ______________________________________

                  TABLE B    ______________________________________     ##STR65##    R.sub.1   Z    ______________________________________    N(CH.sub.3).sub.2               ##STR66##    N(CH.sub.3).sub.2               ##STR67##     ##STR68##               ##STR69##     ##STR70##               ##STR71##     ##STR72##               ##STR73##    NH.sub.2               ##STR74##    NHCH.sub.3               ##STR75##    N(CH.sub.3).sub.2               ##STR76##    N(CH.sub.3).sub.2               ##STR77##    N(CH.sub.3).sub.2               ##STR78##    N(Et).sub.2               ##STR79##    N(Et).sub.2               ##STR80##    NHEt               ##STR81##    NHCH.sub.3               ##STR82##     ##STR83##               ##STR84##    ______________________________________

                  TABLE C    ______________________________________     ##STR85##    R.sub.1   Z    ______________________________________    NH.sub.2               ##STR86##    N(CH.sub.3).sub.2               ##STR87##    NHCH.sub.3               ##STR88##     ##STR89##               ##STR90##     ##STR91##               ##STR92##    NHCH.sub.3               ##STR93##     ##STR94##               ##STR95##    N(CH.sub.3).sub.2               ##STR96##     ##STR97##               ##STR98##     ##STR99##               ##STR100##     ##STR101##               ##STR102##     ##STR103##               ##STR104##     ##STR105##               ##STR106##     ##STR107##               ##STR108##    N(CH.sub.3).sub.2               ##STR109##     ##STR110##               ##STR111##    ______________________________________

                  TABLE D    ______________________________________     ##STR112##    R.sub.1   Z    ______________________________________    N(CH.sub.3).sub.2               ##STR113##     ##STR114##               ##STR115##     ##STR116##               ##STR117##     ##STR118##               ##STR119##     ##STR120##               ##STR121##    N(CH.sub.3).sub.2               ##STR122##    NH.sub.2               ##STR123##     ##STR124##               ##STR125##     ##STR126##               ##STR127##    N(CH.sub.3).sub.2               ##STR128##     ##STR129##               ##STR130##     ##STR131##               ##STR132##     ##STR133##               ##STR134##     ##STR135##               ##STR136##     ##STR137##               ##STR138##     ##STR139##               ##STR140##     ##STR141##              CN     ##STR142##               ##STR143##     ##STR144##              NH.sub.2     ##STR145##              CN     ##STR146##               ##STR147##     ##STR148##              NH.sub.2    ______________________________________

                  TABLE E    ______________________________________     ##STR149##    R.sub.1   Z    ______________________________________    N(CH.sub.3).sub.2               ##STR150##    N(Et).sub.2               ##STR151##     ##STR152##               ##STR153##     ##STR154##               ##STR155##     ##STR156##               ##STR157##     ##STR158##               ##STR159##    ______________________________________

                  TABLE F    ______________________________________     ##STR160##    R.sub.1        Z    ______________________________________     ##STR161##    CN     ##STR162##                    ##STR163##     ##STR164##    NH.sub.2     ##STR165##    CN     ##STR166##                    ##STR167##     ##STR168##    NH.sub.2    ______________________________________

                  TABLE G    ______________________________________     ##STR169##    a       e     R.sub.4    ______________________________________    0       3                   ##STR170##    0       3                   ##STR171##    0       3                   ##STR172##    0       3                   ##STR173##    0       3                   ##STR174##    1       3                   ##STR175##    1       3                   ##STR176##    1       3                   ##STR177##    1       3                   ##STR178##    1       3                   ##STR179##    1       3                   ##STR180##    1       3                   ##STR181##    1       3                   ##STR182##    1       3                   ##STR183##    0       4                   ##STR184##    0       4                   ##STR185##    0       4                   ##STR186##    0       4                   ##STR187##    0       4                   ##STR188##    1       4                   ##STR189##    1       4                   ##STR190##    1       4                   ##STR191##    1       4                   ##STR192##    1       4                   ##STR193##    1       4                   ##STR194##    1       4                   ##STR195##    1       4                   ##STR196##    1       4                   ##STR197##    0       3                   ##STR198##    0       3                   ##STR199##    0       4                   ##STR200##    0       4                   ##STR201##    0       4                   ##STR202##    1       3                   ##STR203##    1       3                   ##STR204##    1       3                   ##STR205##    1       4                   ##STR206##    1       4                   ##STR207##    1       4                   ##STR208##    ______________________________________

                  TABLE H    ______________________________________     ##STR209##    a       e     R.sub.4    ______________________________________    0       3                   ##STR210##    0       3                   ##STR211##    0       3                   ##STR212##    0       3                   ##STR213##    0       3                   ##STR214##    1       3                   ##STR215##    1       3                   ##STR216##    1       3                   ##STR217##    1       3                   ##STR218##    1       3                   ##STR219##    1       3                   ##STR220##    1       3                   ##STR221##    1       3                   ##STR222##    1       3                   ##STR223##    0       4                   ##STR224##    0       4                   ##STR225##    0       4                   ##STR226##    0       4                   ##STR227##    0       4                   ##STR228##    1       4                   ##STR229##    1       4                   ##STR230##    1       4                   ##STR231##    1       4                   ##STR232##    1       4                   ##STR233##    1       4                   ##STR234##    1       4                   ##STR235##    1       4                   ##STR236##    1       4                   ##STR237##    0       3                   ##STR238##    0       3                   ##STR239##    0       4                   ##STR240##    0       4                   ##STR241##    0       4                   ##STR242##    1       3                   ##STR243##    1       3                   ##STR244##    1       3                   ##STR245##    1       4                   ##STR246##    1       4                   ##STR247##    1       4                   ##STR248##    ______________________________________

The compounds of this invention may be prepared by one of the followinggeneral synthetic schemes.

When the bicyclic benzenoid portion of the compound is directly attachedto the X component of Formula I, these compounds may be prepared from abicyclic phenolic (or phenylmercaptan) intermediate shown by FormulaVIII below.

One means of obtaining the appropriately substituted phenolic (or thiol)intermediate of Formula VIII is illustrated in Scheme I. The startingmaterial may be a bicyclic ketone having an oxy or mercaptyl substituentin any one of the four positions possible on the phenyl ring. The ketonecan either be obtained from a commercially available source or preparedaccording to standard procedures known in the art.

The ketone is then converted to the enamine using a primary or secondaryamine in the presence of acid, preferably a Lewis acid such as titaniumtetrachloride. Any polar aprotic solvent may be used in this reaction,for example, toluene or methylene chloride.

The resulting enamine is reduced, preferably using a hydride reagentsuch as a borohydride. Sodium cyanoborohydride is one preferred reducingagent.

The phenolic protecting group is then cleaved to obtain the intermediateof Formula VIII. ##STR249##

The protecting group, P_(R), may be methyl, benzyl or the N-phthalimidoalkyl. If the protecting group is chosen to be other than theN-phthalimido alkyl, the protecting group is removed according tomethods known in the art. If the protecting group is N-phthalimidoalkyl, then it can remain on the synthetic intermediate preceding VIIIand used as in the subsequent reaction step.

The formation of the ether linkage from VIII is accomplished by treatingthe phenolic compound with a protected N-propylbromide in the presenceof a base such as sodium methoxide, potassium t-butoxide or potassiumcarbonate. Ether coupling reagents other than a base and a bromide mayalso be used. (Scheme II) ##STR250##

The nitrogen protecting group is preferably phthalimido but can be anyprotecting group insensitive to the ether formation reaction conditions,such as a base insensitive group.

The amine compound is obtained by the removal of the protecting group,for example, the phthalimido group is removed with hydrazine hydrate.(Scheme III) ##STR251##

An alternate route to compounds of Formula VIII above involves thereduction of the ketonic phenol, followed by the halogenation of theresulting hydroxy compound and the substitution of the desired aminogroup for the halo group. Scheme IV below depicts this reaction sequenceshowing exemplary reagents to effect the desired reactions. ##STR252##

An alternate route for the formation of the ether linkage from VIIIinvolves the base catalyzed reaction of the phenolic compound with anα,ω-dihaloalkyl reagent followed by the nucleophilic displacement of theω-halo substitutent by azide and the reduction of the azido function tothe amine. Scheme V depicts the alternate "azide" route. ##STR253##

Compounds within the scope of Formula I and having a methyleneoxy ormethylenethioxy substituent (d=1)on the phenyl portion of the compoundmay be prepared by one of the reaction sequences described below.

The methyleneoxy or methylenethio ether may be prepared from thecoupling of a 2-bromoethylene phthalimide in the presence of base or2-thioethylamine, respectively, with the methylene hydroxy compound.Scheme VI illustrates the formation of the methylenethio ether.##STR254##

The methyleneoxy compound may be obtained by the reduction of a phenylcarboxylic acid or ester precursor such as IX. The reduction may beconducted by hydrogenation over a rhenium catalyst, by a hydride in thepresence of a Lewis acid or by acidic electrolysis and depending onchoice of conditions may take place before or after the formation of theamine. ##STR255##

If the reduction to the methylene hydroxy compound occurs after theformation of the amine, the carboxylic acid intermediate is preparedanalogously to the phenolic intermediate VIII, with the acid beingprotected by its ester where appropriate.

Compounds within the scope of Formula I, where a is greater than zero,may be prepared by the addition of one or more carbon units at the keto-position of the starting bicyclic ketone compound as shown in SchemeVII. ##STR256##

Treatment of the bicylic ketone with trimethylsilylcyanide and zinciodide forms the cyano trimethylsiloxy adduct in good yield. Treatmentof the siloxy compound with a mixture of a Lewis acid such as tin^(II)chloride and a concentrated halogenic acid such as conc. HCl in glacialacetic acid results in the formation of the carboxylic acid derivative.(See, J. L. Belletire et al, Synth. Commun. 12, No. 10, 763-70 (1982)).An alternative pathway to the carboxylic acid compound which alsoprovides a pathway to amido and amidino derivatives is effected by theuse of tosylmethylisocyanide in the presence of base. For a completediscussion of the one-step conversion of the ketone to the cyanoderivative, see O. H. Oldenziel et al, J. Org. Chem., Vol. 42, No. 19,3114-3117 (1977). The most preferred base is tert-butoxide in anon-polar aprotic solvent such as dimethylsulfoxide or HMPT. Theresulting cyano compound may be hydrolyzed to the acid by means ofaqueous base, for example, aqueous sodium hydroxide, or it may behydrolyzed to the carbamoyl derivative by acidic means including, forexample, BF₃ in glacial acetic acid or aqueous hydrochloric acid.

The mono- or di-substituted amide may be formed by the reaction of theacyl chloride, prepared by treating the acid with SOCl₂ with a primaryor secondary amine, i.e., HNR₂ R₃. The amide may also be formed directlyby a condensation reaction of the acid and amine or through the ester byamide-ester interchange.

Reduction of the amide results in the methylene amine. A hydridereducing agent such as LiAlH₄ in diethyl ether or tetrahydrofuran ispreferred. Other reagents which may be used include LiAlH₄ and AlCl₃ inan ether solvent, boron tetrafluoride etherate in methylene chloridefollowed by sodium borohydride in ethanol, and diborane intetrahydrofuran. These reagents may also be used to obtain the aminedirectly from the cyano intermediate. The preferred reagent is LiAlH4.The amine obtained from the reduction of the nitrile may be alkylated toform the mono-, di- or cyclized derivative using the appropriatealkylating agent, such as an alkyl iodide, alkyl triflate or1,4-dihalo-, 1,5-dihalo-, or 1,6-dihalo-alkl compound. The pyrrolidinyl,1-piperidinyl, morpholinyl and azepinyl compounds may be prepared byalkyating the amine with the appropriate reagents, for example,1,4-dibromobutane or 1,5-dibromopentane.

The amidino derivatives may be prepared from the cyano intermediate.Treatment with anhydrous ethanolic hydrochloric acid forms the ethoxyiminium salt which forms the amidine upon treatment with a primary orsecondary amine as depicted in Scheme VIII. ##STR257##

The ethylene amino and higher alkylene amino compounds according toFormula I may be prepared via the carboxylic acid intermediate by one ormore alkylene chain extending reactions as shown, for example, in SchemeIX. ##STR258##

Reduction of the carboxylic acid, shown in Scheme IX, with a hydridesuch as diborane is followed by the conversion of the resultant hydroxycompound into the halo derivative with a halogenation reagent such aseither SOCl₂ or PBr₃. The chain-extended cyano compound is generated bytreatment of the halo derivative with a cyanide and either can beconverted into the amide, amine or guanidine as described above, or thechain extension process can be continued by conversion via thecarboxylic acid.

Another process for the preparation of compounds within Formula Iwherein a is greater than zero, comprises the formation of spiro cyclicether intermediate by the reaction of an alkylidinyl reagent with acyclic ketone starting material. See Scheme X, below. Rupture of theoxygen containing ring is effected with a nucleophilic nitrogen reagentH--NR₂ R₃. The tertiary hydroxy group is removed via dehydration.Hydrogenation of the unsaturated product is followed by elaboration ofthe phenolic side chain as discussed herein above. ##STR259##

Compounds within the scope of Formula VI (b═c═O) are referred to asbenzocyclobutenes and may be prepared according to the followingreaction sequences.

3-Substituted benzocyclobutenes may be prepared starting from a4-substitued indanone by means of a ring contraction reaction effectedby photolysis of the appropriately substituted diazoindanone. The ringcontraction reaction produced a 1-carboxylic acid benzocyclobutene whichis converted to the 1-aminomethylene compound by reduction to thealcohol followed by the formation and displacement of an appropriateleaving group by the desired nucleophilic amine. Scheme XI below depictsan exemplary reaction sequence. ##STR260##

The Pr group designated in Scheme XI may be any protecting group whichcan be subsequently converted into an amino group by means known topersons skilled in the art.

5-substituted benzocyclobutenes may be prepared starting from apara-alkoxy benzaldehyde which is transformed by condensation withcyanoacetic acid, followed by hydrogenation, decarboxylation andbromination to yield a β-(4-alkoxy-3-bromophenyl)propionitrile. Thebromo compound is cyclized to the benzocyclobutene and converted to the1-aminomethylene benzocyclobutene by reactions described herein above.Scheme XII below depicts an exemplary sequence. ##STR261##

The addition of the terminal R₄ group comprises treating the amine withan R₄ end group precursor unit including those groups listed in SchemeXIII. The preparation of the precursors of the R₄ groups and thereaction conditions under which they are coupled to the primary amineare fully described in U.S. Pat. Nos. 4,104,381, 4,279,819, 4,323,566,4,390,701, 4,395,553, and GB No. 2047238A, GB No. 2067987A, and EPOPublication No. 0081955A2, hereby incorporated by reference. ##STR262##

When Z is NH₂, CN or sulfamoyl amidine, the reaction sequence isslightly modified as shown below in Scheme XIV. Reaction of the phenolicintermediate with a cyano-substituted alkylating agent such as3-cyanopropylchloride in the presence of a base produces the cyano ethercompound. Reduction of the cyano group with a hydride such as lithiumaluminum hydride results in the amino compound. Treatment of the cyanocompound with anhydrous methanolic HCl yields an imidate intermediatewhich is converted to the sulfonyl amidine by treatment with a sulfamidein methanol. For a complete discussion of this preparatory sequence, seeU.S. Pat. No. 4,283,408, incorporated herein by reference. ##STR263##

The analogous mercaptan compounds may be prepared by reacting a cyanomercaptan with the appropriate halomethylene intermediate as shown inScheme XV below. The amino sulfonyl amidine compound is prepared byreaction sequences similar to those described above. ##STR264##

The compounds of this invention may be readily converted to theirnon-toxic acid addition salts by customary methods in the art. Thenon-toxic salts of this invention are those salts the acid component ofwhich is pharmacologically acceptable in the intended dosages, includingthose prepared from inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, andfrom organic acids such as methane sulfonic acid, benzenesulfonic acid,acetic acid, propionic acid, malic acid, oxalic acid, succinic acid,glycolic acid, lactic acid, salicyclic acid, benzoic acid, nicotinicacid, phtalic acid, stearic acid, oleic acid, abietic acid, etc.

The following are selected examples of the preparation of the compoundsaccording to this invention.

EXAMPLE 1 Preparation of3-amino-4-[3-[7-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1,2,5-thiadiazole-1-oxide

Step 1. 7-(3-Phthalimidopropoxy)-tetralone.

7-Hydroxy-1-tetralone (33.3 g) is dissolved in dimethylformamide (325ml) and the mixture is cooled in an ice bath. Sodium methoxide (11.07 g)is added to the mixture. After the mixture is stirred for 3 min.,N-(3-bromopropyl) phthalimide (54.96 g) is added to the mixture;stirring is continued and the reaction mixture stirred overnight. Theresulting mixture is poured into H₂ O (650 ml), stirred for 1 hour,filtered, washed with H₂ O and air dried. The resulting fluffy nearwhitesolid (62.8 g) is crystallized from ethyl acetate to give the desiredproduct, a fluffy white solid (M.P. 149°-150° C.)

Step 2. 1-Dimethylamino-7-(3-phthalimido)propoxy-3,4-dihydronaphthalene.

A solution of titanium tetrachloride (5.4 g) in toluene (20 ml) is addedover a period of 15 minutes to a stirred solution of 7-(3-phthalimido)propoxy-1-tetralone (19.9 g) suspended in a solution of anhydrousdimethyl amine (22 g) in dry toluene (200 ml) while maintaining areaction temperature of about 1° C. under a N₂ atmosphere. When theaddition is complete, the reaction mixture is allowed to warm to RT andstirred at RT for 41/2 hours. The reaction mixture is filtered, thesalts washed with dry toluene and the clear filtrate evaporated,affording a light yellow oil, which is stored under N₂ and used in thenext step without any further treatment.

Step 3. 1-Dimethylamino-7-(3-phthalimido)propoxy-1,2,3,4-tetrahydronaphthalene.

Anhydrous hydrogen chloride gas (3.3 g) is bubbled into a stirredreaction mixture of the phthalimido enamine obtained in the previousstep in anhydrous tetrahydrofuran (210 ml) resulting in the productionof a large amount of precipitate. Sodium cyanoborohydride (2.3 g) in drymethanol (50 ml) is added to the stirred suspension over a period of 5minutes under a stream of N₂. When addition is complete, the reactionmixture is stirred at RT for 21/2 hours, evaporated in vacuo, and theresidue partitioned between ether and 2% KOH solution. The layers areseparated and the aqueous layer extracted with additional ether. Thecombined ether layers are washed with H₂ O and then stirred with 5%aqueous HCl solution. The layers are separated and the aqueous acidwashed with ether. The acidic layer is made strongly alkaline with 50%sodium hydroxide solution, resulting in the formation of an oilyprecipitate which is extracted with ether. The ether extract is washedwith saturated sodium chloride solution, dried over magnesium sulfate,and evaporated in vacuo, yielding 15.9 g of a clear yellow oil. NMRanalysis indicates this oil to be the desired product, which is usedwithout further treatment for the following reaction.

Step 4.7-(3-Aminopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene.

85% hydrazine hydrate solution (3.2 ml) is added to a solution of thephthalimido tetrahydronaphthalene (about 15 g) obtained in the precedingstep dissolved in absolute ethanol (160 ml). The stirred reactionmixture is refluxed for 3 hours, after which it is allowed to cool andthe resulting precipitate removed by filtration. The clear yellowfiltrate is evaporated in vacuo leaving a moist yellow solid, which istriturated in 5% aqueous HCl solution. The resulting thick slurry isfiltered and the clear filtrate made strongly alkaline with 50% sodiumhydroxide solution, resulting in the formation of an oily precipitate.The precipitate is extracted with diethyl ether and the ether layerswashed with saturated sodium chloride solution, dried over sodiumsulfate, filtered and the filtrate evaporated in vacuo, yielding 7.8 gof a light amber oil. NMR and IR analysis indicate that this oil is thedesired amino product, which is used without further treatment for thenext reaction step.

Step 5. 3-Amino-4-[3-[7-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propylamino-1,2,5-thiadiazole-1-oxide.

3,4-Dimethoxy-1,2,5-thiadiazole-1-oxide (4.46 g) is dissolved inmethanol (450 ml) and the methanolic solution cooled to 3° C. in an icebath. 7-(3-aminopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene(7.2 g) in 75 ml methanol is slowly added to the stirred mixture andstirring continued at a constant temperature of 3° C. for one hour afteraddition is complete. Anhydrous ammonia (31 g) is bubbled into thereaction mixture and stirring is continued at RT for 2 hours. Thereaction mixture is evaporated in vacuo and the residue triturated inethyl acetate (75 ml), stirred in ethyl acetate for 1.5 hours, filtered,washed with ethyl acetate and diethyl ether, and dried in vacuo yieldinga white powder (8.2 g), M.P. 154°-158° C., comprising more than onecompound.

The powder is dissolved in a solution of 10% methanol/methylenechloride, and chromatographed on a silica gel column (250 g; 100-200mesh) eluting the column with successively more polar solventcombinations of methanol in CH₂ Cl₂ (10% to 60% methanol). The fractionscontaining the material with Rf of 0.11 are pooled and evaporated invacuo, yielding a white solid (3.6 g), which is triturated in ether,filtered and dried, giving 3.2 g of a white powder, M.P. 160°-163° C.(dec). NMR, IR and elemental analysis indicate that this material is thedesired thiadiazole-1-oxide product.

EXAMPLE 2 The Preparation of3-amino-4-[3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthloxy)]-propylamino]-1,2,5-thiadiazole-1-oxide

Step 1. 5-[3-(N-Phthalimido)propoxy]-1-tetralone.

75.9 g of anhydrous potassium carbonate is added to a stirred solutionof 5-hydroxy-1-tetralone (89.1 g) in dimethylformamide (890 ml). Thereaction mixture is stirred for 15 minutes, at which time 147 g ofN-(3-bromopropyl) phthalimide is added to the reaction mixture. Themixture is stirred at RT overnight. The reaction mixture is extractedwith H₂ O and methylene chloride. The methylene chloride extracts arewashed with H₂ O, dried over sodium sulfate, filtered, and the filtrateevaporated in vacuo, yielding a dark viscous oil. The oil is dissolvedin ethyl acetate, seeded, and allowed to stir at RT for two hours. Theresultant solid is filtered, washed with 150 ml ethyl acetate, andallowed to air dry, yielding 72.4 g of a tan solid, M.P. 119°-121° C.

Step 2. 1-Dimethylamino-5-(phthalimido) propoxy-3,4-dihydronaphthalene.

A solution of dimethylamine (40.1 g) in dry toluene (350 ml) is added toa stirred suspension of the tetralone obtained in Step 1 (35 g)suspended in dry toluene (150 ml) under positive N₂ pressure. Theresultant mixture is cooled in an ice bath to 1° C., followed by theaddition of titanium tetrachloride (5.5 ml) in dry toluene (40 ml) overa period of 20 minutes, maintaining a temperature of <0° C. After theaddition is complete, the ice bath is removed and the mixture allowed towarm to RT. After stirring for 41/2 hours, the mixture is filtered, thesalts washed with 400 ml dry toluene and the clear light yellow filtrateevaporated in vacuo, yielding 47 g of a slightly cloudy red-orange oilwhich is used in the next step without further treatment.

Step 3. 1-Dimethylamino-5-(3-phthalimido)propoxy-1,2,3,4-tetrahydronaphthalene

The dihydronaphthalene of the previous step is dissolved in 350 ml ofanhydrous tetrahydrofuran and introduced into a reaction flask under N₂.Anhydrous hydrogen chloride (5.9 g) is passed into the stirred solutionunder N₂, followed by the addition of sodium cyanoborohydride (4.0 g) indry methanol (100 ml) over a period of 10 minutes, resulting in a lightyellow cloudy suspension. The suspension is stirred under N₂ at RT forabout 3 hours. The reaction mixture is evaporated in vacuo at 40°-50°C., and the residue partitioned between 0.1N KOH solution and diethylether. The aqueous layer is extracted with ether, and the combinedorganic extracts washed with H₂ O and stirred with 5% aqueous HClresulting in the formation of a precipitate. The solid is filtered andwashed with diethyl ether and 5% HCl. The aqueous filtrate is combinedwith the solid and the mixture made strongly alkaline. The resultantsolution is extracted with diethyl ether. The combined ether extractsare washed with saturated sodium chloride, dried over sodium sulfate,filtered and the filtrate evaporated in vacuo. The resultant viscousamber oil is identified by NMR as the desired product, which is usedwithout further purification for the next step of the reaction sequence.

Step 4.5-(3-Aminopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene.

4.4 ml of 99% hydrazine hydrate are added to a stirred solution of5-(3-phthalimidopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene(26.8 g prepared in the preceding step) in absolute ethanol (270 ml).The reaction mixture is stirred and heated to reflux for 3 hours,allowed to cool, filtered and the filtrate evaporated in vacuo. Theyellow residue is triturated in 5% HCl (250 ml), the suspension filteredand the solid washed with 5% HCl. The clear yellow filtrate is extractedwith diethyl ether. The aqueous acidic layer is made strongly alkalinewith 50% NaOH solution, resulting in an oily precipitate which isextracted with diethyl ether. The combined organic extracts are driedover sodium sulfate, filtered and the filtrate evaporated in vacuo,yielding 14.7 g of a light yellow oil identified by NMR as the desired3-aminopropoxy compound.

Step 5.3-Amino-4-[3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]]propylamino-1,2,5-thiadiazole-1-oxide.

7.0 g of5-(3-aminopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene, whichis obtained in the preceding step, in methanol (70 ml) is added over aperiod of 1 hour and 10 minutes to a solution of3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (4.57 g) in methanol (450 ml)and stirred under N₂ at a temperature of 2° C. for one hour. Anhydrousammonia (26 g) is bubbled into the reaction mixture over a period of 10minutes. The ice bath is removed and the reaction mixture allowed towarm at RT for two hours, after which the resultant mixture isevaporated in vacuo, yielding 11 g of a yellow solid. The yellow solidis suspended in absolute methanol (90 ml) and the suspension heated toboiling for 10 minutes. The cooled suspension is stirred at RT for onehour, filtered, washed with ethanol and ether, and dried at 60° C. (0.25mm Hg) for two hours. The resultant light yellow powder has a meltingpoint of 198°-199° C. NMR, IR and elemental analysis indicate that thesolid is the desired product.

EXAMPLE 3 The Preparation ofn-[3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]-propyl]-n'-methyl-2-nitro-1,1-diaminoethene

3.58 g of 2-methylamino-2-methylthio-1-nitroethene is added to asolution of 3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)propylamine (6 g) in absolute ethanol (60 ml). The stirred reactionmixture is refluxed for two hours, while purging the atmosphere abovethe reaction mixture with N₂ to remove evolved methyl mercaptan. Thereaction mixture is allowed to cool to RT while stirring for anadditional hour. The resultant solid is filtered, washed with ethanoland ether, and dried in a vacuum dessicator at 60°-70° C. for 11/2hours, yielding 4.2 g of a near-white solid, M.P. 160°-164° C.Recrystallization from ethanol results in a white solid, M.P. 161°-165°C. NMR, IR, and elemental analysis indicate that this solid is thedesired product.

EXAMPLE 4 The Preparation of3-amino-4-[3-[5-[1-(1-piperidinyl)]-1,2,3,4-tetrahydronaphthyloxy]]propylamino]-1,2,5-thiadiazole-1-oxide

Step 1.1-(1-Piperidinyl)-5-(3-phthalimido)propoxy-3,4-dihydronaphthalene.

83.8 ml of piperidine are added to a stirred suspension of5-(3-phthalimido)propoxy-1-tetralone (36.9 g) in dry toluene (370 ml)under N₂. The reaction mixture is stirred at RT for several minutes andthen cooled in an ice bath to about 1° C. 5.8 ml of titaniumtetrachloride in toluene (50 ml) is added to the reaction mixture over aperiod of 25 minutes, maintaining the temperature at 4°-6° C. The icebath is removed after the addition is complete. The reaction mixture isstirred for four hours, filtered and the solid washed with dry toluene(300 ml). The filtrate is evaporated in vacuo yielding 47.6 g of a darkred-orange viscous oil. NMR indicates that this oil is the desireddihydronaphthalene product.

Step 2.1-(1-Piperidinyl)-5-(3-phthalimido)propoxy-1,2,3,4-tetrahydronaphthalene.

The red oil obtained in the previous step is dissolved in anhydroustetrahydrofuran (350 ml) under an atmosphere of Na₂. 5.9 g of anhydrousHCl is bubbled into the solution over a period of about two minutes,resulting in a solid precipitate. Maintaining a positive N₂ pressure,the suspension is stirred and 4.2 g of sodium cyanoborohydride in drymethanol (100 ml) is added over a period of 10 minutes. After theaddition is complete, the reaction mixture is stirred at RT for a periodof 3 hours, after which N₂ is bubbled vigorously through the mixture for10 minutes. The mixture is evaporated in vacuo at 40°-45° C. and theresidue partitioned between aqueous base and ether. The resulting solidsare filtered away and the filtrate layers separated. The aqueous layeris washed with ether and the combined ether extracts washed with H₂ Oand saturated sodium chloride and dried over sodium sulfate. Thecombined ether extracts are filtered and the filtrate evaporated invacuo affording 38.2 g of a slightly cloudy orange oil. NMR indicatesthat the orange oil is the desired product, which is used withoutfurther treatment for the next step of the reaction sequence.

Step 3.5-(3-Aminopropoxy)-1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthalene.

The orange oil from the preceding step is stirred with absolute ethanol(375 ml) and the ethanol supernatant decanted from the insolublematerial. 6.5 ml of an 85% hydrazine hydrate solution is added to theethanol solution and the reaction mixture refluxed for three hours. Thecooled mixture is filtered and the filtrate evaporated in vacuo,yielding a yellow solid foam. The yellow solid is triturated with 5%aqueous HCl, the solids filtered away and the filtrate made stronglyalkaline with sodium hydroxide solution. The resulting oily precipitateis extracted with diethyl ether and the organic extract dried oversodium sulfate. The ether solution is filtered and the filtrateevaporated in vacuo affording 21.2 g of an amber oil. Distillation ofthis oil in vacuo yields two fractions boiling below the range of ≦180°C. (0.5 mm Hg) to 290° C. (0.5-0.7 mm Hg). These fractions wereidentified as the desired end product by NMR analysis. (Succinate salt;M.P. =161°-163° C.)

Step 4.3-Amino-4-[3-[5-[1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthyloxy]]propylamino]-1,2,5-thiadiazole-1-oxide

5-(3-Aminopropoxy)-1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthalene (7.3g), obtained in the previous step, in methanol (75 ml) is added over aperiod of 45 minutes to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (4.1 g) in methanol (410 ml)while maintaining a reaction temperature of 2°-3° C. under an atmosphereof N₂. After the addition is complete, the solution is stirred in theice bath for 30 minutes, followed by the addition of 20.7 g of anhydrousammonia gas bubbled into the reaction mixture over a period of fiveminutes. The reaction mixture is stirred at RT overnight and theresultant mixture evaporated in vacuo, resulting in 10.7 g of a foamyoil. The oil is dissolved in 10% methanol in methylene chloride (100 ml)and purified on a silica gel column (100-200 mesh; 400 g) using eluentshaving increasingly greater percentages of methanol. The major fractionsare pooled, yielding 3.6 g of a foamy solid. The foamy solid istriturated with boiling absolute ethanol and the cooled solution isfiltered. The solid is washed with ethanol and ether and dried at65°-70° C. at 0.5 mm Hg for two hours, yielding 1.85 g of a white solidhaving a melting point of 204°-205° C. NMR analysis and elementalanalysis identify the white solid as the desired thiadiazole oxide endproduct.

EXAMPLE 5

Preparation of3-amino-5-[3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole

Step 1. 5-(3-N-Phthalimidopropoxy)-1-tetralone

Potassium carbonate (94.5 g) is added to a solution of5-hydroxy-1-tetralone (111 g) dissolved in dimethylformamide (1 liter)and the solution stirred for about 15 minutes. 183.3 g ofN-(3-bromopropyl) phthalimide are added to the stirred solution, and thereaction mixture is stirred at RT overnight. The reaction mixture ispartitioned between H₂ O and methylene chloride, and the aqueous layersextracted with methylene chloride. The combined organic layers arewashed with H₂ O and dried over sodium sulfate. The organic extract isfiltered and the filtrate evaporated in vacuo, yielding a viscous oilwhich is dissolved in ethyl acetate and stirred at RT for 2 hours. Theresultant solid is filtered and dried in air, yielding about 90 g of ayellowish solid, M.P. 118°-121° C. NMR indicates that the solid is thedesired phthalimido product.

Step 2. 1-Dimethylamino-5-(3-phthalimidopropoxy)-3,4-dihydronaphthalene.

5-(3-N-Phthalimidopropoxy)-1-tetralone (50 g) is suspended in 120 ml ofanhydrous toluene. 57.4 g of dimethylamine in toluene (500 ml) are addedto the stirred suspension and the mixture cooled to 1° C. A solution oftitanium tetrachloride (7.92 ml) in toluene (60 ml) is added slowly tothe stirred suspension, keeping the temperature below 6° C. After theaddition is complete, the reaction mixture is allowed to reach RT andstirred for three hours. The reaction mixture is filtered, the filteredsalts washed with dry toluene, and the filtrate evaporated in vacuo,yielding 55.7 g of a viscous yellow liquid. NMR indicates that thisproduct is predominently the desired end product, which is used in thefollowing step without any further treatment.

Step 3.1-Dimethylamino-5-(3-phthalimidopropoxy)-1,2,3,4-tetrahydronaphthalene.

The viscous yellow liquid obtained in the preceding step (55.7 g) isdissolved in anhydrous tetrahydrofuran (450 ml) and anhydrous hydrogenchloride gas (5.9 g) passed through the solution. A gummy precipitateresults. The reaction mixture is stirred while 5.6 g of sodiumcyanoborohydride in dry methanol (120 ml) is added over a period of tenminutes, resulting in a yellow suspension. The suspension is stirredunder N₂ at RT for 3 hours and the resultant mixture evaporated invacuo, yielding 57.4 g of a viscous yellow liquid. The liquid ispartitioned between aqueous base and diethyl ether. The aqueous layersare washed with ether and the combined ether layers washed with H₂ O.The ether extract is stirred with 350 ml of 5% HCl and the resultingprecipitate filtered and washed successively with 5% HCl and diethylether. The aqueous phases are made strongly alkaline and extracted withether. The combined ether phases are washed with saturated sodiumchloride and dried over sodium sulfate, filtered and evaporated invacuo, yielding 35 g of crude product, which NMR indicates is primarilythe desired tetrahydronaphthalene compound and which is used withoutfurther treatment in the next reaction step.

Step 4.5-(3-Aminopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene.

6.7 ml of hydrazine hydrate is added to a solution of the crude productobtained in the previous reaction step dissolved in ethanol (400 ml).The reaction mixture is stirred under reflux for 3 hours and allowed tostir at RT overnight. The reaction mixture is filtered, the filteredsolid washed with ethanol, and the filtrate evaporated in vacuo,affording a yellow solid. The solid is treated with 5% HCl (250 ml), theresulting suspension filtered, and the filtrate extracted with diethylether. The aqueous portion is made basic, resulting in the formation ofa yellow oil. The aqueous portion is extracted with diethyl ether andthe combined ether extracts dried over sodium sulfate, filtered andevaporated in vacuo, yielding 17 g of a viscous yellow liquid. NMRanalysis indicates that the crude product is the desired aminopropoxytetrahydronaphthalene.

Step 5.1-Cyano-3-[3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propyl]-2-methylpseudothiourea.

9.9 g of the amine obtained in the previous step in isopropyl alcohol(25 ml) are added over a period of ten minutes to a solution ofS,S-dimethyl-N-cyanoiminodithiocarbonimidate (6.5 g) in isopropanol (100ml). The reaction mixture is stirred at RT overnight and evaporated invacuo, yielding a green oil. TLC and IR spectra indicate that this oilis the desired product, which is used in the next step without furthertreatment.

Step 6.3-Amino-5-[3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole.

4.5 g of methyl hydrazine is added to a stirred solution of thecyanopseudothiourea obtained in the preceding step (about 6 g) indimethylformamide (60 ml). The reaction mixture is stirred for about 20hours at a temperature of 40° C., after which it is evaporated in vacuo,yielding 13 g of a brown oil. The oil is triturated in anhydrous ether,filtered and dried, yielding 4.9 g of a green powder consisting of 2major products. The green powder is dissolved in 10% methanol andmethylene chloride and run through a silica gel column (200 g) elutingthe column with successively more polar combinations of methanol andmethylene chloride. The major product fractions are pooled andevaporated in vacuo, resulting in 2.6 g of a light brown solid, which istriturated in boiling acetonitrile, cooled and filtered. The solid iswashed with acetonitrile and diethyl ether and dried at elevatedtemperature in vacuo, resulting in the desired triazole product as anear-white powder, M.P. 171°-173° C.

EXAMPLE 6 The Preparation of2-cyano-1-[3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propyl]-3-methylguanidine

10.5 g of anhydrous methylamine in absolute ethanol (75 ml) is combinedwith a solution of1-cyano-3-[3-[5-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propyl]-2-methylpseudothiourea(about 6 g) in absolute ethanol (100 ml). The reaction mixture isstirred at RT overnight while purging with N₂ to remove the methylmercaptan. The reaction mixture is evaporated in vacuo, yielding 8.0 gof a dark oil, which is separated on a silica gel column (375 g), elutedwith methanol in methylene chloride at increasingly greaterconcentrations of methanol (10% to 40%). The major pure fractions arepooled together and evaporated in vacuo, resulting in 4.1 g of a brownglass. The glass is dissolved in 50 ml of methanol and 2.1 g ofO-benzoic sulfimide added to the solution. The resulting solution isevaporated in vacuo, yielding a dark oil which is triturated inanhydrous ether, the resultant solid filtered, washed with ether andallowed to air dry. The resulting solid has a melting point of 160°-165°C. The solid is dissolved in hot methanol, filtered while hot, allowedto cool, and the resultant solution diluted with an equal volume ofanhydrous ether. The resultant solid is filtered, washed withmethanol/diethyl ether (1:1), diethyl ether and air dried, yielding 3.5g of a light gray solid, M.P. 171°-173° C., with shrinkage beginning at169° C. NMR, IR and elemental analysis indicate that this solid is thedesired 2-cyano guanidine saccharinate.

EXAMPLE 7 The Preparation of3-amino-5-[3-[5-[1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthloxy]]propylamino]-1-Methyl-1H-1,2,4-triazole

Step 1.1-Cyano-2-methyl-3-[3-[5-[1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthyloxy]]propyl]pseudothiourea.

2.9 g of5-(3-aminopropoxy)-1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthylene inisopropanol (15 ml) are added over a period of 3 minutes to a stirredsolution of S,S-dimethyl-N-cyanoiminodithiocarbonimidate (1.6 g)dissolved in isopropanol (20 ml). The reaction mixture is stirred at RTovernight, resulting in the formation of a solid precipitate. The solidis filtered, washed with isopropanol and diethyl ether, and dried in airand at 0.75 mm Hg, resulting in 2.9 g of a white powder, M.P. 141°-144°C. NMR and elemental analysis indicate that the white powder is thedesired product.

Step 2.3-Amino-5-[3-[5-[1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthyloxy]]propylamino]-1-methyl-1H-1,2,4-triazole.

Methyl hydrazine (2 ml) is added to a stirred suspension of thepseudothiourea obtained in the previous step (2.40 g) suspended indimethylformamide (20 ml). The reaction mixture is heated and stirred ata temperature between 40°-45° C. for 24 hours. The reaction mixture isallowed to cool and evaporated in vacuo. The moist residue is trituratedwith anhydrous diethyl ether, the resultant solid filtered, washed withether and allowed to air dry, yielding a white powder which is twicerecrystallized from ethyl acetate and dried, M.P. 165.5°-167° C. NMR, IRand elemental analysis indicate that this product is the desiredtriazole.

EXAMPLE 8 The Preparation ofn-[3-[7-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)propyl]-N'-methyl-2-nitro-1,1-diaminoethene

Step 1. 1-Dimethylamino-7-methoxy-3,4-dihydronaphthalene.

A solution of titanium tetrachloride (53.8 g, 31.2 ml) in dry toluene(200 ml) is added over a period of 45 minutes to a stirred solution of7-methoxy-1tetralone (100.5 g) and dimethyl amine (171 g) in dry toluene(2 l) while maintaining a reaction temperature of ≦10° C. When theaddition of the titanium is complete, the ice bath is removed and thesolution allowed to reach RT. The solution is stirred at RT for 3 hours.The solids are filtered, washed with dry toluene and the filtrateevaporated in vacuo, yielding 101.4 g of an amber oil which is used inthe next step without further treatment.

Step 2. 7-Methoxy-1-dimethylamino-1,2,3,4-tetrahydronaphthalene.

A solution of 95% sodium cyanoborohydride (22.5 g) in methanol (500 ml)is added slowly to a stirred solution of the methoxy dihydronaphthaleneof the previous step in tetrahydrofuran (1.6 l) to which has previouslybeen added anhydrous hydrochloric acid (23.4 g). The addition isaccomplished under an atmosphere of N₂. The reaction mixture is stirredat RT for 3 hours, N₂ vigorously bubbled through the reaction mixtureand the mixture evaporated in vacuo, yielding a cloudy oil. The oil istaken up in 2% KOH (1 liter) and partitioned between base and dietherether. KOH pellets are added until the aqueous layer is made basic, thelayers separated, and the aqueous layer washed with ether. The combinedether extracts are washed with H₂ O and stirred with 5% HCl for 15minutes. The acidic layer is washed with ether and then made basic with50% sodium hydroxide solution. The resultant aqueous layer is extractedwith ether, the ether extract dried over sodium sulfate, filtered andevaporated in vacuo, yielding about 90 g of a gold oil identified by NMRand IR as the desired tetrahydronaphthalene product.

Step 3. 7-Hydroxy-1-dimethylamino-1,2,3,4-tetrahydronaphthalene.

90 g of 7-methoxytetrahydronaphthalene obtained in the previous step aredissolved in glacial acetic acid (1 liter). 48% hydrobromic acid (1liter) is added to the solution and the resulting reaction mixtureheated to reflux for 3 hours. The reaction mixture is poured into 4liters of H₂ O and crushed ice and the solution made alkaline to pH 8 to9. The aqueous mixture is extracted with methylene chloride. Themethylene chloride extract is back-extracted with 2% KOH solution andthe combined basic layers made acidic by the addition of aqueous HCl.The addition is continued until a white precipitate appears at pH about8-9. The aqueous solution is extracted with methylene chloride and theorganic layer washed with H₂ O, dried, filtered and evaporated in vacuo,yielding a brown oil identified by NMR to be the desired phenol.

Step 4. 1-Dimethylamino-7-[3-(N-phthalimido)propoxy]-1,2,3,4-tetrahydronaphthalene.

Potassium t-butoxide (3.0 g) is added to a stirred solution of1-dimethylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene (5.2 g) indimethylformamide (50 ml). 13.2 g of N-(3-bromopropyl) phthalimide isadded to the stirred reaction mixture and stirring continued for about24 hours. The reaction is partitioned between slightly basic H₂ O anddiethyl ether. The layers are separated and the aqueous layer extractedwith ether. The combined ether extracts are washed with 5% sodiumhydroxide solution and H₂ O. The ether extract is stirred with 5%aqueous hydrochloric acid solution, the layers separated and the etherextracted with additional aqueous 5% hydrochloric acid. The combinedacidic aqueous layers are washed with ether and made strongly alkaline,resulting in an oily precipitate. The precipitate is extracted withdiethyl ether which is washed with H₂ O and saturated sodium chloridesolution dried and evaporated in vacuo, yielding 4.4 g of a light yellowglassy solid. NMR analysis indicates that the solid is the desiredtetrahydronaphthalene product.

Step 5.7-(3-Aminopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene.

85% hydrazine hydrate (9.6 ml) is added to a stirred solution of thephthalimido tetrathydronaphthalene prepared as described in the previousstep (about 50 g) in absolute ethanol (about 500 ml). The reactionmixture is heated at reflux for about 3 hours and allowed to cool. Theresulting precipitate is removed by filtration and washed with absoluteethanol. The filtrate is evaporated in vacuo and the residue trituratedwith 5% aqueous hydrochloric acid. The aqueous suspension is filteredand the solid washed with 5% hydrochloric acid. The filtrate is madestrongly alkaline with 50% sodium hydroxide solution, resulting in anoily precipitate which is extracted into diethyl ether. The etherextract is washed with saturated sodium chloride solution, dried,filtered and the filtrate evaporated in vacuo, yielding 28.5 g of thedesired amine as an amber oil. NMR, IR and elemental analysis verify theamine structure.

Step 6. N-[3-[7-(1-Dimethylamino-1,2,3,4-tetrahydronaphthyloxy)propyl]-N'-methyl-2-nitro-1,1-diaminoethene.

1-Methylamino-1-methylthio-2-nitroethene (3.58 g) is added to a solutionof the tetrahydronaphthyloxy amine prepared in the preceding step (6.0g) in absolute ethanol (60 ml). The reaction mixture is heated to refluxfor about 2 hours while purging the reaction mixture with N₂. Themixture is allowed to cool and the resultant solid filtered, washed withdiethyl ether and dried, yielding about 2.9 g of a white solid. Thefiltrate is evaporated in vacuo and the residue dissolved in hotabsolute ethanol. Diethyl ether is added, resulting in the formation ofa solid which is filtered and dried, giving 1.4 g of a white solid, M.P.148°-152° C. The two solids are combined and dissolved in boilingisopropyl alcohol, allowed to cool, filtered, washed with isopropylalcohol and ether, and dried under vacuum. The resulting white powder(2.7 g) has a melting point of 153°-157° C. NMR and elemental analysisidentify the solid as the desired diaminoethene product.

EXAMPLE 9 The Preparation of3-amino-5-[3-[7-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole

Step 1. 7-(3-N-Phthalimidopropoxy)-1-tetralone.

Sodium methoxide (19.8 g) is added to a cooled, stirred solution of7-hydroxy-1-tetralone (59.5 g) dissolved in dimethylformamide (600 ml).After addition is complete and reaction mixture is stirred for 3minutes, N-(3-bromopropyl) phthalimide (98.3 g) is added and thereaction mixture stirred overnight. The reaction mixture is poured intoH₂ O and stirred for an hour, filtered, the solid washed with H₂ O anddried in air to give 134 g of a brown solid. The brown solid isrecrystallized from hot ethyl acetate, yielding 43.5 g of a white fluffysolid, M.P. 148°-150° C. NMR identifies the recrystallized product asthe desired phthalimide.

Step 2.1-Dimethylamino-7-(3-N-phthalimidopropoxy)-3,4-dihydronaphthalene.

7-(3-N-Phthalimidopropoxy)-1-tetralone (93.5 g) is suspended in asolution of dimethyl amine (101.3 g) in toluene (1 liter) under N₂. Thestirred suspension is cooled to about 1° C. and titanium tetrachloride(14.6 ml, 25.2 g) in toluene (100 ml) is added to the stirred suspensionover a period of 45 minutes, keeping the temperature below 7° C. Afteraddition is complete, the reaction mixture is allowed to reach RT andstirred for 41/2 hours. The reaction mixture is filtered and thefiltered solid washed with dry toluene. The toluene filtrate isevaporated in vacuo, yielding about 100 g of a yellow oily liquid,identified by NMR as the desired product.

Step 3.1-Dimethylamino-7-(3-N-phthalimidopropoxy)-1,2,3,4-tetrahydronaphthalene.

Sodium cyanoborohydride (10.2 g) in dry methanol (150 ml) is addedslowly with stirring to a solution of the phthalimido dihydronaphthaleneprepared in the preceding step (about 100 g) in anhydroustetrahydrofuran (550 ml) in which 16 g of anhydrous hydrogen chloride isdissolved. At the end of the addition, the reaction mixture comprises afine suspension and is stirred at RT for 3 hours under N₂. The reactionmixture is evaporated in vacuo, resulting in a viscous liquid which ispartitioned between 5% potassium hydroxide solution and diethyl ether.The layers are separated and the basic layer washed with ether. Theether extracts are combined and stirred with 5% HCl. The aqueous layeris washed with ether and then made strongly basic with 50% sodiumhydroxide solution. The basic aqueous extract is washed with ether andthe ether extract washed with sodium chloride, dried, filtered and theether solution evaporated in vacuo to yield a pale yellow solid. NMRindicates that this solid is the desired tetrahydronaphthalene product.

Step 4.1-Dimethylamino-7-(3-aminopropoxy)-1,2,3,4-tetrahydronaphthalene.

Hydrazine hydrate (3.56 g) is added to a solution of thetetrahydronaphthalene obtained in the preceding step dissolved in 180 mlof absolute ethanol. The reaction mixture is stirred and heated toreflux for 3 hours. The resultant solid is filtered and the filtrateevaporated in vacuo, yielding a pale yellow solid. The solid istriturated with 5% HCl, the resultant thick slurry filtered, and thesolid washed with 5% HCl. The acidic phase is made strongly basic withsodium hydroxide solution until a gold oil appears. The solution isextracted with ether, the ether washed with saturated sodium chloridesolution and dried over sodium sulfate. The sodium sulfate is filteredand the ether evaporated in vacuo, resulting in the desired amineproduct as a viscous oil.

Step 5.1-Cyano-3-[3-[7-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propyl]-2-methylpseudothiourea.

The amine obtained in the preceding step (8.6 g) dissolved inisopropanol (35 ml) is added over a period of one minute to a stirredsolution of S,S-dimethyl-N-cyanoiminodithiocarbonimidate (5.6 g)dissolved in 70 ml of isopropanol. The reaction mixture is stirred at RTovernight and then evaporated in vacuo, yielding 13.6 g of the desiredcyano product as a viscous amber oil.

Step 6.3-Amino-5-[3-[7-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole.

Methyl hydrazine (11 ml) is added to a stirred solution of thecyanotetrahydronaphthalene obtained in the previous step (about 10 g)dissolved in dimethylformamide (110 ml). The reaction mixture is stirredat about 40° C. for 24 hours, and evaporated under vacuum resulting in aresidue of amber oil (16.2 g). The oil is separated on a silica gelcolumn (290 g; 70-230 mesh) using as eluent methanol in methylenechloride ranging from 10% methanol to 30% methanol. The major fractionsare pooled and evaporated in vacuo, resulting in 6.7 g of a viscousamber oil. The oil is triturated in anhydrous ether, resulting in theformation of a solid which is filtered, washed with ether and dried,resulting in 5.4 g of a near-white solid, M.P. 120°-125° C. This solidis recrystallized from hot acetonitrile and dried under vacuum,resulting in 3.5 g of a near-white powder, M.P. 127°-130° C. NMR, IR andelemental analysis indicate the solid as the desired triazole product.

EXAMPLE 10 The Preparation of3-amino-4-]3-[6-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1,2,5-thiadiazole-1-oxide

Step 1. 6-(3-N-Phthalimidopropoxy)-1-tetralone.

77.5 g of N-bromopropylphthalimide are added to a stirred solution of6-hydroxy-1-tetralone (48.6 g) and potassium carbonate (39.9 g) indimethylformamide (480 ml). The reaction mixture is stirred at RTovernight, and then poured into a stirred mixture of H₂ O and methylenechloride. The layers are separated and the aqueous portion washed withmethylene chloride. The combined methylene chloride fractions are washedwith H₂ O, dried over sodium sulfate, filtered and the filtrateevaporated in vacuo, yielding an off-white solid which is recrystallizedfrom absolute ethanol, yielding 73.1 g of crystals, M.P. 143°-145° C.Step 2.1-Dimethylamino-6-(3-N-phthalimidopropoxy)-3,4-dihydronaphthalene.

Dimethylamine (81.6 g) in dry toluene (600 ml) is added to a stirredsuspension of 6-(3-N-phthalimido- propoxy)-1-tetralone (71.3 g) in drytoluene (200 ml) kept at a temperature of 0° C. under N₂. Titaniumtetrachloride (19.3 g, 11.2 ml) in dry toluene (80 ml) is added slowlyto the stirred suspension, keeping the temperature of the reactionmixture below 10° C. The reaction mixture is stirred under N₂ overnight,after which it is filtered, the salts washed with dry toluene and thefiltrate evaporated in vacuo, yielding 85.9 g of a yellow viscous liquidused as is in the next step without further purification.

Step 3.1-Dimethylamino-6-(3-N-phthalimidopropoxy)-1,2,3,4-tetrahydronaphthalene.

Sodium cyanoborohydride (9.26 g of 95%) in dry methanol (220 ml) isadded slowly to a vigorously stirred mixture of the dihydronaphthaleneobtained in the previous step (85.9 g) dissolved in tetrahydrofuran (600ml) in which anhydrous hydrogen chloride (15 g) has been dissolved. Thereaction mixture is stirred at RT overnight under N₂. Another 200 ml ofmethanol is added to the reaction mixture and nitrogen gas bubbledthrough the mixture for 10 minutes. The resulting solution is evaporatedin vacuo, yielding a brown oil which is partitioned between aqueous baseand diethyl ether. The aqueous layer is washed with ether and thecombined ether portions washed with H₂ O and stirred with aqueous 5%HCl. The resultant precipitate is filtered and combined with theseparated aqueous layer. The aqueous layer is made alkaline andextracted with ether, and the combined ether portions are washed withsaturated sodium chloride and H₂ O, dried over sodium sulfate andfiltered. The filtrate is evaporated, resulting in 52 g of a viscousyellow liquid. NMR analysis indicates that the yellow liquid is thedesired tetrahydronaphthalene.

Step 4. 1-Dimethylamino-(3-aminopropoxy)-1,2,3,4-tetrahydronaphthalene.

80% hydrazine hydrate (10.0 ml) is added to a stirred solution of thephthalimido tetrahydronaphthalene obtained in the previous step (52 g)dissolved in absolute ethanol (500 ml). The reaction mixture is refluxedfor 3 hours, allowed to cool, and the resultant solid filtered and thefiltrate evaporated in vacuo. The yellow solid residue is trituratedwith aqueous 5% HCl, filtered, washed with aqueous HCl, and the filtrateextracted with ether. The acidic aqueous portion is made basic with 50%sodium hydroxide. The resultant diphasic mixture is extracted withether, the ether extracts dried, filtered, and evaporated, yielding ayellow viscous liquid (30.1 g). The liquid is dried under high vacuum,yielding 27.7 g of the crude product, which is used as is in the nextstep.

Step 5.3-Amino-4-[3-[6-(1-dimethylamino-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1,2,5-thiadiazole-1-oxide

1-Dimethylamino-(3-aminopropoxy)-1,2,3,4-tetrahydronaphthalene (7.0 g)in methanol (70 ml) is added over a period of 1 hour to a stirredsolution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (4.57 g) in methanol(450 ml) cooled to a temperature of 2° C. under N₂. Anhydrous ammonia(30 g) is bubbled over a period of 10 minutes into the reaction mixtureand the solution stirred at RT overnight. The reaction mixture isevaporated in vacuo, yielding a yellow solid (10.4 g). The solid isdissolved in 10% methanol and methylene chloride mixed with Celite andfiltered. The cloudy filtrate is evaporated in vacuo, yielding a glasswhich is chromatographed on a column of silica gel (350 g) eluting thecolumn with methanol in methylene chloride ranging from a methanolpercentage of 10% to 60% methanol. The fractions having an Rf of 0.07are pooled and evaporated in vacuo, yielding 3.5 g of a dark oil. Theoil is triturated in ether, the solid filtered, washed with ether anddried in high vacuum, giving 2.76 g of a near-white powder, M.P.149°-152° C. The powder is dissolved in hot absolute ethanol and ether,the gummy precipitate filtered, and the filtrate evaporated in vacuo,triturated in ether, filtered, and the solid dried under high vacuum,giving 2.1 g of a near-white powder, M.P. 157°-159° C. (dec). NMR, IRand elemental analysis indicate the desired product.

EXAMPLE 11 Preparation of3amino-4-[3-[5-[[1-(n-morpholinyl)]-1,2,3,4-tetrahydronaphthyloxyp]]propylamino]-1,2,5-thiadiazole-1-oxide

Step 1. 5-Methoxy-(1-(N-morpholinyl))-3,4-dihydronaphthalene.

Titanium tetrachloride (15.2 g) in dry toluene (105 ml) is added slowlyto a stirred solution of 5-methoxy-1-tetralone (49 g), and morpholine(160 g) in dry toluene (1 l) cooled in an ice bath to a temperature of3° C. under a nitrogen atmosphere. The reaction mixture is allowed towarm to RT and stirred at RT under N₂ overnight. The reaction mixture isfiltered, the filtered solid washed with dry toluene and dry THF and thecombined filtrates evaporated in vacuo to a yellow solid (63.5 g), M.P.80°-90° C.

Step 2. 5-Methoxy-1-(N-morpholinyl)-1,2,3,4-tetrahydronaphthalene.

95% sodium cyanoborohydride (10.2 g) in methanol (225 ml) is added to astirred reaction mixture of the 5-methoxy dihydronaphthalene obtained inthe previous step (about 63 g) and 11.7 g of anhydrous hydrochloric aciddissolved in anhydrous tetrahydrofuran (1 liter). The reaction mixtureis stirred at RT for 3 hours, N₂ gas vigorously bubbled through thereaction mixture and the resulting suspension evaporated in vacuo,yielding a whitish solid. The solid residue is partitioned betweenaqueous base and methylene chloride, the alkaline layer washed withmethylene chloride and the combined methylene chloride portions washedwith H₂ O. The methylene chloride extract is stirred with aqueous 5%HCl, the layers separated and the organic layer again washed withaqueous 5% HCl. The aqueous layer is made extremely basic with 50%sodium hydroxide solution and the basic solution extracted withmethylene chloride. The methylene chloride extract is washed with H₂ O,dried, filtered, and the filtrate evaporated in vacuo, yielding 18.3 gof an oil which later solidifies. NMR analysis indicates that the crudeproduct is the desired compound, which is used without further treatmentin the next synthetic step.

Step 3. 5-Hydroxy-1-morpholinyl-1,2,3,4-tetrahydronaphthalene.

48% hydrobromic acid (180 ml) is added to a stirred solution of thecrude tetrahydronaphthalene obtained in the previous step (18.3 g)dissolved in glacial acetic acid (180 ml) under an atmosphere of N₂. Thereaction mixture is refluxed under N₂ for 3 hours, after which it ispoured into crushed ice, resulting in the formation of a greenprecipitate. The precipitate is filtered and the filtrate extracted withether. The aqueous layer is made basic (pH 8-9) forming a whiteprecipitate. The precipitate is extracted with ether, the layersseparated, and the ether portion washed with H₂ O, dried over sodiumsulfate, filtered and evaporated in vacuo, resulting in a whitecrystalline solid (14.9 g), M.P. 194°-196° C. NMR indicates the desiredphenolic product.

Step 4.5-(3-Phthalimidopropoxy)-1-(N-morpholinyl)-1,2,3,4-tetrahydronaphthalene.

Potassium t-butoxide (7.8 g) is added to a stirred solution of5-hydroxy-1-morpholinyl-1,2,3,4-tetrahydronaphthalene (14.7 g) dissolvedin dimethylformamide (150 ml) and the reaction solution stirred for afew minutes. N-(3-bromopropyl) phthalimide (33.8 g) is added to thereaction mixture and stirring is continued at RT for 2 days. Thereaction mixture is partitioned between H₂ O and ether, the layersseparated and the aqueous layer adjusted to a pH>10 with sodiumhydroxide solution and extracted with additional diethyl ether. Thecombined ether layers are washed with H₂ Oand aqueous 5% hydrochloricacid. The acidic aqueous extracts are made strongly alkaline with sodiumhydroxide solution, resulting in an oily precipitate which is extractedwith ether and methylene chloride. The combined organic layers arewashed with 5% aqueous sodium hydroxide and saturated sodium chloride,dried over sodium sulfate, filtered, and evaporated, resulting in 22.6 gof an amber oil as the crude product used in the next step.

Step 5.5-(3-Aminopropoxy)-1-(N-morpholinyl)-1,2,3,4-tetrahydronaphthalene.

85% hydrazine hydrate (3.3 ml) is added to a suspension of thephthalimido tetrahydronaphthalene obtained in the preceding step (21.9g) in absolute ethanol (200 ml). The reaction mixture is heated toreflux with stirring for 31/2 hours, after which the reaction mixture isallowed to cool, filtered and the solid washed with ethanol. The ethanolfiltrate is evaporated in vacuo, yielding 3.4 g of a solid. The solidand residue are combined and stirred with 5% aqueous HCl, the mixturefiltered and the solid washed with 5% HCl. The filtrate is made stronglyalkaline with 50% sodium hydroxide solution, resulting in the formationof an oily precipitate which is extracted with methylene chloride. Themethylene chloride extract is washed with saturated sodium chloridesolution, dried over sodium sulfate, filtered and evaporated in vacuo,yielding 13.2 g of an amber oil which is identified by NMR analysis tobe the desired amine product.

Step 6.3-Amino-4-[3-[5-[1-(N-morpholinyl)-1,2,3,4-tetrahydronaphthyloxy]]propylamino]-1,2,5-thiadiazole-1-oxide

5-(3-Aminopropoxy)-1-(N-morpholinyl)-1,2,3,4-tetrahydronaphthalene (6.3g) in methanol (60 ml) is added over a period of one hour to a stirredsolution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (3.35 g) in methanol(350 ml), cooled in an ice bath under an atmosphere of N₂. The reactionmixture is stirred in an ice bath for 21/2 hours, followed by theaddition of anhydrous ammonia (25.0 g) bubbled into the reaction mixtureover a period of 10 minutes. The solution is stirred at RT for 2 hours,after which the reaction mixture is evaporated in vacuo, resulting in9.3 g of a solid. The solid is ground into a powder and suspended inabsolute ethanol. The suspension heated to boiling, cooled, and thecooled suspension filtered. The solid is washed with ethanol and ether,and dried under vacuum, giving 4.8 g of a white solid, M.P. 198°-200° C.(dec). NMR and elemental analysis establish this solid as the desiredtriazole product.

EXAMPLE 12 PREPARATION OF3-AMINO-5-[3-[5-[[1-(N-MORPHOLINYL)]-1,2,3,4-TETRAHYDRONAPHTHYLOXY]]PROPYLAMINO]-1-METHYL-1H-1,2,4-TRIAZOLE

A mixture of5-(3-aminopropoxy)-1-(N-morpholinyl)-1,2,3,4-tetrahydronaphthalene (5.2g) and the methyl ester ofN-cyano-1-methyl-2-(phenylmethylene)hydrazinecarboxyimidothioic acid(4.0 g) is heated neat to a temperature of 70° C. in a vacuum of 15 mmHg for a period of 41/2 hours. The resultant neat mixture is cooled andtriturated in acetone, resulting in a solid precipitate. The addition of5% aqueous hydrochloric acid affords a clear light-green solution whichis stirred at RT for an hour, diluted with H₂ O and washed with diethylether. The aqueous solution is made strongly alkaline with 50% sodiumhydroxide solution resulting in an oily precipitate, which is extractedwith ethyl acetate. The ethyl acetate extract is washed with saturatedsodium chloride, dried over sodium sulfate, filtered and the filtrateevaporated in vacuo, resulting in 6.9 g of a viscous amber oil. The oilis dissolved in hot acetonitrile, filtered, the acetonitrile solutionallowed to cool, and the resultant precipitate filtered, yielding 3.38 gof a solid, M.P. 150°-153° C. NMR, IR and elemental analysis indicatethe solid to be the desired triazole product.

EXAMPLE 13

PREPARATION OF3-AMINO-4-[3-[5-(1-PYRROLIDINYL-1,2,3,4-TETRAHYDRONAPHTHYLOXY)]PROPYLAMINO]-1,2,5-THIADIAZOLE-1-OXIDE

Step 1. 5-Methoxy-1-pyrrolidinyl-3,4-dihydronaphthalene.

Titanium tetrachloride (31.1 ml) in dry toluene (210 ml) is added slowlyto a stirred solution of 5-methoxy-1-tetralone (100 g) and pyrrolidine(263 g) in anhydrous toluene (2 1) cooled in a methanol ice bath underN₂ while maintaining a temperature of less than 7° C. When the additionis complete, the reaction mixture is allowed to stir at RT for 31/2 hrs.The reaction mixture is filtered, the solid washed with anhydroustoluene, and the filtrate evaporated in vacuo, resulting in a goldviscous liquid, which is dissolved in 1.8 l of dry tetrahydrofuran andfiltered. The filtrate is used as is in the next step.

Step 2. 5-Methoxy-1-pyrrolidinyl-1,2,3,4-tetrahydronaphthalene.

Anhydrous hydrochloric acid in methanol (23 g) is added to the filtrateobtained in the previous step, while stirring the mixture under N₂.Sodium cyanoborohydride (22.7 g) in methanol (180 ml) is added slowly tothe reaction mixture with vigorous stirring. The resultant suspension isstirred under N₂ for almost 3 hrs at RT, nitrogen gas is bubbled throughthe solution and the solution evaporated in vacuo. The resultant viscousliquid is taken up in aqueous base and diethyl ether. The aqueous layeris made strongly basic with solid potassium hydroxide and the layersseparated. The aqueous layer is washed with ether and the ether portionscombined and stirred with 5% aqueous hydrochloric acid solution. Theether portion is separated and washed with additional hydrochloric acidsolution. The combined aqueous portions are made alkaline, resulting inthe formation of an immiscible liquid which is extracted with ether. Theether extract is washed with H₂ O, dried and evaporated in vacuo,resulting in a solid identified as the desired material. The solid isused in the next step without purification.

Step 3. 5-Hydroxy-1-pyrrolidinyl-1,2,3,4-tetrahydronaphthalene.

48% hydrobromic acid (1 l) is added to a stirred solution of the methoxytetrahydronaphthalene obtained in the previous step dissolved in glacialacetic acid (1 l) under an atmosphere of nitrogen. The reaction mixtureis heated to reflux for 2 hrs, then poured into H₂ O/crushed ice andsodium hydroxide pellets added until a white solid appears. Aqueous baseis used to adjust the pH to about 8 to 9. The mixture is filtered, andthe filtered solid is ground and suspended in H₂ O and filtered again.The solid is recrystallized from ethyl acetate, yielding a whitishsolid, M.P. 151°-153° C. NMR analysis indicates that the product is thedesired 5-hydroxy-tetrahydronaphthalene.

Step 4.5-(3-N-Phthalimidopropoxy)-1-N-pyrrolidinyl-1,2,3,4-tetrahydronaphthalene.

Potassium t-butoxide (30.9 g) is added to a solution of5-hydroxy-1-(N-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalene (65.3 g) indimethylformamide (650 ml). The reaction mixture is stirred for 5minutes, after which N-(3-bromopropyl) phthalimide (134.5 g) is added tothe reaction mixture. Stirring is continued over the weekend. Thereaction mixture is diluted with H₂ O and extracted with ether. Theaqueous portion is made basic with 50% sodium hydroxide solution andagain extracted with ether. The combined ether extracts are washed withH₂ O, stirred with 5% sodium hydroxide solution, the basic layersback-extracted with ether and the combined ether extracts washed with H₂O and stirred with 5% aqueous hydrochloric acid solution. The layers areseparated and the ether washed with 5% aqueous hydrochloric acidsolution and the combined aqueous acid extracts made alkaline with 50%sodium hydroxide solution, resulting in a white precipitate. Theprecipitate is extracted with ether and methylene chloride and theaqueous portion extracted with methylene chloride. The combined organicextracts are dried, filtered and evaporated in vacuo, resulting in 67.1g of a pinkish solid. The solid is recrystallized from ethanol,filtered, dried in vacuo, yielding about 51 g of dry product, which isused without further purification in the next step.

Step 5.5-(3-Aminopropoxy)-1-(N-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalene.

85% hydrazine hydrate (8.3 ml) is added to a stirred solution of thephthalimido pyrrolidinyl tetrahydronaphthalene obtained in the previousstep (about 51 g) dissolved in absolute ethanol (500 ml), and thereaction mixture is heated to reflux for 3 hours and then allowed tocool. A precipitate forms upon cooling, and the reaction mixture isfiltered, the precipitate washed with absolute ethanol, and the filtrateevaporated in vacuo, resulting in a solid. The solid is triturated with5% aqueous HCl, filtered, and the solid washed with additional 5% HClsolution. The acidic filtrate is washed with diethyl ether and madebasic with 50% aqueous sodium hydroxide, resulting in the formation of agolden oil. The oil is extracted with diethyl ether, washed with H₂ O,dried over sodium sulfate, filtered and evaporated in vacuo, resultingin 17 g of a golden oil. NMR analysis indicates that this oil is thedesired amino product.

Step 6.3-Amino-4-[3-[5-(1-pyrrolidinyl-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1,2,5-thiadiazole-1-oxide.

5-(3-Aminopropoxy)-1-(N-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalene (7.0g) in methanol (100 ml) is added over a period of 90 minutes to astirred solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (4.14 g) inmethanol (450 ml), while maintaining the temperature at less than 3° C.The reaction mixture is stirred for an additional 11/2 hours, afterwhich anhydrous ammonia is bubbled into the reaction mixture over aperiod of 10 minutes. The reaction mixture is stirred at ambienttemperature overnight, evaporated in vacuo, yielding 9.9 g of anoff-white solid. The solid is triturated with ethyl acetate, filtered,and the solid dissolved in 10% methanol in methylene chloride. Themethanolic solution is placed on a silica gel column (silica gel: Kieselgel 60, 70-230 mesh) and eluted with successively higher concentrationsof methanol in methylene chloride ranging from 10 to 30%. The majorfractions are pooled together and evaporated in vacuo, yielding 6.5 g ofa solid which is recrystallized from ethanol, yielding 3 g of a yellowsolid, M.P. 184°-186° C. NMR, IR and elemental analysis indicate thedesired thiadiazole-1-oxide product.

EXAMPLE 14 PREPARATION OF 3-AMINO-4-[3-[6-(1-DIMETHYLAMINOINDANYLOXY)]PROPYLAMINO]-1,2,5-THIADIAZOLE-1-OXIDE

Step 1. 1-Dimethylamino-6-methoxy-1,2-indene.

Titanium tetrachloride (11.5 g) in toluene (50 ml) is added over aperiod of 20 minutes to a stirred solution of 6-methoxy-1-indanone (19.6g), anhydrous dimethylamine (32 g) in anhydrous toluene (350 ml) underan atmosphere of N₂, while maintaining a temperature of less than 9° C.After the addition is complete, the reaction mixture is a light greenslurry, which is stirred at RT for 3 hours, filtered, and the filtrateevaporated in vacuo, yielding 23.2 g of a green oil. NMR indicates that80-85% of the oil is the desired eneamine, which is used without furthertreatment in the next step.

Step 2. 1-Dimethylamino-6-methoxy indan.

A solution of anhydrous HCl (4.3 g) in THF (40 ml) is added to a stirredsolution of the indene obtained in the previous step (23.0 g) inanhydrous THF (350 ml) under an atmosphere of N₂. Sodiumcyanoborohydride (4.32 g) in methanol (75 ml) is added to the stirredreaction mixture over a period of 15 minutes, and the reaction mixtureis stirred at RT under N₂ for an additional 4 hours. Nitrogen isvigorously bubbled through the reaction mixture for several minutes,after which it is evaporated in vacuo and the residue partitionedbetween methylene chloride and aqueous base. The layers are separatedand the aqueous layer extracted with methylene chloride. The combinedmethylene chloride fractions are washed with H₂ O and stirred with 5%aqueous HCl. The combined acidic aqueous fractions are washed withmethylene chloride and then made strongly alkaline with 50% sodiumhydroxide solution, resulting in an oily precipitate. The precipitate isextracted with methylene chloride and the methylene chloride extractwashed with saturated sodium chloride, dried over sodium sulfate,filtered and the filtrate evaporated in vacuo, giving 14.9 g of a brownoil, identified as the desired product by NMR analysis. This oil is usedwithout further treatment for the next step.

Step 3. 1-Dimethylamino-6-hydroxy indan.

A mixture of 1-dimethylamino-6-methoxy indan (14.6 g) and 48%hydrobromic acid (140 ml) in glacial acetic (140 ml) is refluxed withstirring under N₂ for 3 hours. The cooled reaction mixture is pouredinto crushed ice and the pH adjusted to about 8-9 with 50% sodiumhydroxide solution, resulting in the formation of an oil and a darksolid precipitate. The aqueous mixture is extracted with methylenechloride, the methylene chloride extract washed with H₂ O and saturatedsodium chloride solution, dried over sodium sulfate, filtered and thefiltrate evaporated in vacuo, resulting in 9.6 g of a brown solid. Thebrown solid is dissolved in boiling toluene and the slightly cloudysupernatant decanted from a dark oily material. The toluene solution iscooled resulting in the formation of a precipitate which is filtered andallowed to air dry, resulting in 6.85 g of a beige crystalline solid,

44° C. NMR indicates this to be the desired M.P. 141°-144° C. NMRindicates this to be the desired product, which is used without furthertreatment for the next reaction.

Step 4. 1-Dimethylamino-6-(3-N-phthalimidopropoxy) indan.

Potassium t-butoxide (4.3 g) is added to a stirred solution of thephenol obtained in the previous step (6.1 g) in dimethylformamide (60ml). N-(3-bromopropyl) phthalimide (18.5 g) is added to the stirredsolution, resulting in the formation of a brown suspension. The reactionmixture is stirred at RT for 48 hours. The reaction mixture ispartitioned between ether and H₂ O, the layers separated and the aqueouslayer made more basic with 50% sodium hydroxide solution, andsubsequently extracted with additional ether. The combined ether layersare washed with H₂ O and stirred with 5% aqueous HCl. The ether layer isagain washed with 5% aqueous HCl and the combined aqueous layers washedwith methylene chloride. The acidic phase is made strongly alkaline with50% sodium hydroxide solution and extracted with methylene chloride. Themethylene chloride is washed with aqueous base and H₂ O, dried oversodium sulfate, filtered and evaporated in vacuo, yielding 5.9 g of anamber oil, identified by NMR and IR analysis to be the desiredphthalimido product.

Step 5. 6-(3-Aminopropoxy)-1-dimethylamino indan.

85% hydrazine hydrate solution (1.1 ml) is added to a suspension of6-(3-N-phthalimidopropoxy)-1-dimethylamino indan (5.8 g) in absoluteethanol (55 ml). The reaction mixture is stirred at reflux for 3 hours,allowed to cool, and the mixture filtered. The filtered solid is washedwith ethanol, the filtrate evaporated in vacuo and the residuetriturated with 5% aqueous hydrochloric acid. The triturated solid isfiltered and washed with 5% HCl. The filtrate is washed with ether andmade strongly alkaline with 50% sodium hydroxide solution, resulting inthe formation of an oily precipitate. The oil is extracted with diethylether and the ether washed with saturated sodium chloride solution. Thecombined aqueous layers are back-extracted with methylene chloride. Thecombined organic extracts are dried over sodium sulfate, filtered andthe filtrate evaporated affording 3.2 g of an amber oil, identified byNMR to be the desired amine product.

Step 6.3-Amino-4-[3-[6-(1-dimethylaminoindanyloxy)]propylamino]-1,2,5-thiadiazole-1-oxide.

6-(3-Aminopropoxy)-1-dimethylamino indan (3.1 g) in methanol (60 ml) isadded over a period of 90 minutes to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (2.15 g) in methanol (200 ml)under an atmosphere of N₂, while maintaining the reaction temperature atabout 5° C. The reaction mixture is stirred for 21/2 hours, after whichanhydrous ammonia (20 g) is bubbled into the reaction mixture over aperiod of 5 minutes. The reaction mixture is allowed to react RT andstirred under N₂ overnight. The reaction mixture is evaporated in vacuo,affording 4.8 g of a foam which is dissolved in 5% methanol andmethylene chloride and stirred at RT for 2 hours. The resulting cloudysolution is filtered and evaporated in vacuo. The residue is dissolvedin 10% methanol in methylene chloride, placed on a silica gel column(150 g; 70-230 mesh) and eluted with successive concentrations ofmethanol in methylene chloride (10% to 40% methanol). The majorfractions are pooled and evaporated in vacuo, resulting in 3.5 g of afoam, which is stirred in diethyl ether overnight. The resultingsuspension is filtered and the solid washed with ether and dried at 60°C. at 5 mm Hg for 3 hours, resulting in 3.1 g of a white powder, M.P.160°-162° C. (dec). NMR, IR and elemental analysis indicate that thewhite powder is the desired thiadiazole product.

EXAMPLE 15

THE PREPARATION OF3-AMINO-5-[3-[4-(1-PIPERIDINYLINDANYLOXY)]PROPYLAMINO]-1-METHYL-1H-1,2,4-TRIAZOLE

Step 1. 4-Methoxy-1-indanone.

Methyl iodide (69 ml) is added dropwise over a period of 15 minutes to astirred mixture of 4-hydroxy-1-indanone (150 g) and anhydrous potassiumcarbonate (154 g) dissolved in DMF (1.5 liter) cooled to 0° C. undernitrogen. The reaction mixture is stirred at RT for 24 hours andpartitioned between methylene chloride and water. The methylene chloridefraction is washed with water and 2% aqueous NaOH and dried over Na₂SO₄. The dried extract is filtered, concentrated in vacuo and theresidue dissolved in hot methanol which upon cooling forms aprecipitate. The precipitate is filtered and recrystallized frommethanol yielding the methoxy product as a solid, M.P. 104°-106° C.

Step 2. 1-Hydroxy-4-methoxyindan.

Sodium borohydride (9.65 g) is added over a period of 15 minutes to astirred suspension of 4-methoxy-1-indanone (127.3 g) in ethanol (650 ml)at a temperature of 24° C. under nitrogen. The reaction mixture isrefluxed for 2 hours, cooled and glacial acetic acid (15 ml) added. Theresulting mixture is concentrated in vacuo and the residue partitionedbetween ether and water. The ether extract is washed with water,saturated sodium bicarbonate, saturated salt, dried over Na₂ SO₄,filtered and concentrated in vacuo yielding the hydroxy compound as asolid, M.P. 77.5°-79.5° C.

Step 3. 1-Chloro-4-methoxyindan.

Anhydrous hydrogen chloride is bubbled for 3 hours into a stirredmixture of 1-hydroxy-4-methoxyindan (117.9 g), calcium chloride (120 g,4-20 mesh), and anhydrous toluene (2 l). The reaction mixture isdecanted and filtered and the filtrate and supernatant evaporatedyielding a brown oil which is used in the next step without furtherpurification.

Step 4. 4-Methoxy-1-piperidinylindan.

A solution of 1-chloro-4-methoxyindan (from Step 3) in chloroform (130ml) is added over a period of ten minutes to a stirred mixture ofpiperidine (284 ml) in chloroform (400 ml) under nitrogen. The reactionmixture is heated to reflux for six hours and allowed to stand at RTovernight. The mixture is treated with 10% aqueous HCl and the organiclayer separated. The aqueous layer is extracted with methylene chlorideand the combined organic extracts washed with 10% aqueous HCl. Theorganic layer is evaporated in vacuo and the residue partitioned between5% aqueous HCl and ether. The combined aqueous fraction is washed withether, made alkaline, and the alkaline layer extracted with ether. Theether extract is washed, dried and concentrated in vacuo yielding thepiperidine indan as an oil.

Step 5. 4-Hydroxy-1-piperidinylindan.

Hydrobromic acid (47-49%, 750 ml) is added to a stirred solution of the4-methoxy-1-piperidinylindan (75 g) in glacial acetic acid (750 ml)under nitrogen. The mixture is refluxed for four hours, allowed to cooland poured into crushed ice and water. The pH of the ice mixture isadjusted to about 9 and the aqueous mixture extracted with methylenechloride. The methylene chloride extract is washed with water therebyforming a precipitate which is filtered and the solid dried. Themethylene chloride layer is evaporated yielding an oil. The solid isdissolved in acetonitrile and treated with charcoal. The oil is treatedwith charcoal and dissolved in acetonitrile. Both dissolved materialsare recrystallized from acetonitrile yielding the desired product, M.P.134.5°-136.5° C.

Step 6. 4-(3-Bromopropyl)-1-piperidinylindan.

Potassium hydroxide (53 g, 87%) is added over a period of 1 hour 15 minto a stirred suspension of 4-hydroxy-1-piperidinylindan (30 g), andtetrabutylammonium chloride (4.1 g) in 1,3-dibromopropane (140 ml) andthe resulting mixture stirred at RT under nitrogen for two hours. Thereaction mixture is partitioned between ice-water and ether and theaqueous layer separated and extracted with ether. The combined organicextracts are washed with water and ice cold 5% aqueous HCl forming aprecipitate which is filtered and washed with ether. The acidic fractionis made strongly alkaline forming an oil precipitate which is extractedinto ether. The combined ether layers are washed, dried over Na₂ SO₄,filtered and concentrated in vacuo yielding the desired product as anoil which is used in the next step without further treatment.

Step 7. 4-(3-Azidopropoxy)-1-piperidinylindan.

Sodium azide (7.84 g) is added to a stirred solution of3-bromopropoxy-1-piperidinylindan (40 g from Step 6 above) inethanol/water (800 ml/80 ml) and the mixture heated to reflux for 24hours. The reaction mixture is partitioned between water and methylenechloride and the organic layer separated, washed, dried, filtered andevaporated in vacuo yielding the desired azide indan as an oil.

Step 8. 4-(3-Aminopropoxy)-1-piperidinylindan.

A solution of the azido indan (38 g) (of Step 7 above) in ether (250 ml)is added over a period of 30 min to a suspension of LAH in anhydrousether (1.5 1) stirred under nitrogen. The mixture is refluxed for about1.5 hours then cooled and 6 ml H₂ O added. Aqueous NaOH (15% solution, 6ml) is added followed by H₂ O (18 ml) and stirring continued for about1.5 hours. The reaction mixture is filtered, the solid washed with etherand the filtrate dried over Na₂ SO₄, filtered and concentrated in vacuo.The residue is dissolved in methylene chloride, dried, filtered andevaporated yielding the desired product as an oil.

Step 9.3-Amino-5-[3-[4-(1-piperidinylindanyloxy)propylamino]-1-methyl-1H-1,2,4-triazole.

A mixture of 5-(3-aminopropoxy)-1-(1-piperidinyl)indan (4.7 g) andmethyl-N-cyano-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate(3.98 g) is stirred neat under vacuum at 70°-78° C. for about 3.5 hours.The reaction mixture is allowed to cool and 100 ml of a 5% aqueousHCl/acetone (60:40) solution is added dropwise to the reaction mixtureover a period of one hour. 100 ml of water is added to the mixture whichis washed with ether. The aqueous mixture is alkalinized with NaOHsolution and the resulting oil extracted with ethyl acetate. The organicextract is washed, dried over Na₂ SO₄, filtered and the filtrateevaporated yielding a solid which is recrystallized from hotacetonitrile and dried under vacuum giving the desired product, M.P.135°-136.5° C.

EXAMPLE 16 THE PREPARATION OFN-[3-[4-(1-PIPERIDINYLINDANYLOXY)]PROPYL]-1,2-BENZISOTHIAZOL-3-AMINE-1,1-DIOXIDE

A solution of 3-chlorobenzoisothiazole-1,1-dioxide (2.42 g) inchloroform (100 ml) is added over a period of about one hour to arefluxing solution of 5-(3-aminopropoxy)-1-(1-piperidinyl)-indan (3.0 g)in chloroform (300 ml) under nitrogen. The reaction mixture is refluxedfor an additional hour, evaporated in vacuo, and the residue istriturated with a mixture of hot ethanol and triethylamine. Theprecipitate is filtered, the filtrate evaporated in vacuo and theresultant solid is dissolved in methanol and chromatographed on silicagel (100 g, 230-400 mesh) eluting with methanol. The fractions showingR_(f) =0.24 by tlc are combined and evaporated. The residue istriturated in ethyl acetate, filtered and the solid dried under vacuumyielding the desired product as a solid, M.P. 209°-212° C.

The following compounds may be prepared by analagous reaction pathwaysutilizing the corresponding starting materials and reagents.

3-Amino-5-[3-[5-(1-pyrrolidinyl-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole;M.P.=177°-179° C.

3-Amino-5-[3-[4-(1-diethylaminoindanyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole.1/4H₂ O; M.P.=142°-144° C.

3-Amino-5-[3-[6-(1-piperidinylindanyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole; M.P.=141°-144° C.

3-Amino-5-[4-[5-(1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy)]butylamino]-1-methyl-1H-1,2,4-triazoleM.P.=115°-118° C.

3-Amino-4-[3-[6-(1-piperidinylindanyloxy)]propylamino]-1,2,5-thiadiazole-1-oxide;M.P.=184°-186° C.

1-Cyano-3-[3-[5-(1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy)]propyl]-2-methylpseudothiourea;M.P.=145°-146° C.

5-(2-Aminoethoxy)-1-piperidinyl-1,2,3,4-tetrahydronaphthalene;M.P.=89°-92° C.

1-Cyano-3-[3-[5-1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy)]ethyl]-2-methylpseudothiourea; M.P.=185°-187° C.

3-Amino-5-[3-[5-(1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-benzyl-1H-1,2,4-triazole;(glass).

3-Amino-5-[2-[5-(1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy)]ethylamino-1-methyl-1H-1,2,4-triazole.1/4 H₂ O; M.P.=79°-81° C.

3-Amino-5-[3-[5-(1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-ethyl-1H-1,2,4-triazole;M.P.=186°-187° C.

3-Amino-5-[2-[4-(1-piperidinylindanyloxy)]ethylamino]-1-methyl-1H-1,2,4-triazolemethanesulfonate;M.P.=204°-207° C.

3-Amino-4-[3-[4-(1-piperidinylindanyloxy)]propylamino]-1,2,5-thiadiazole-1-oxide;M.P.=184°-187° C.

EXAMPLE 17 THE PREPARATION OF1-AMINO-2-[3-[4-(1-1-PIPERIDINYLINDANYLOXY)]PROPYLAMINO]CYCLOBUTENE-3,4-DIONE

A solution of 5-(3-aminopropoxy)-1-1-piperidinylindan (3.82 g) inmethanol (40 ml) is added to a stirred solution of 1,2-dimethoxycyclobutene-3,4-dione (1.98 g) in methanol (40 ml) cooled in an ice bathunder a nitrogen atmosphere. The reaction mixture is allowed to warm toRT, stirred at RT for 2 hours and cooled to ice bath temperature. Anexcess of anhydrous ammonia is bubbled into the reaction mixture whichis allowed to warm to RT and stirred overnight at RT. The reactionmixture is filtered and the solid precipitate washed with methanol andether, dried under vacuum and recrystallized from DMF. The crystallineproduct is dried at elevated temperature in vacuo yielding the desiredproduct as a white powder, M.P. 240°-242° C. (dec).

EXAMPLE 18 THE PREPARATION OF1-AMINO-2-[3-[5-[1-(1-PIPERIDINYL)-1,2,3,4-TETRAHYDRONAPHTHYLOXY]PROPYLAMINO]-CYCLOBUTENE-3,4-DIONE

A solution of3-[5-(1-piperidinyl)-1,2,3,4-tetrahydronaphthyloxy]propylamine (3.69 g)in methanol (40 ml) is added dropwise to a stirred solution of1,2-dimethoxy-cyclobutene-3,4-dione (1.8 g) in methanol (40 ml) cooledto 5° C. Excess anhydrous ammonia is bubbled into the cooled mixture for5-10 min and stirring is continued at RT for about 18 hours. Thereaction mixture is filtered, the solid washed with methanol and driedat 60° C. in vacuo, yielding the desired product, M.P. 242°-245° C.(dec) (discolors at about 220° C.)

EXAMPLE 19 THE PREPARATION OF3-HYDROXYMETHYL-5-[3-[5-[1-(1-PIPERIDINYL)-1,2,3,4-TETRAHYDRONAPHTHYLOXY]PROPYLAMINO]]-1-METHYL-1H-1,2,4-TRIAZOLE

Step 1.1-Acetoxyacetyl-2-methyl-2-[phenylmethyleneamino]-3-[3-[5-[1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthyoxy]]propyl]guanidine.

A neat mixture ofMethyl-N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate(6.39 g) and5-(3-aminopropoxy)-1-piperidinyl-1,2,3,4-tetrahydronaphthalene (6.0 g)is heated under house vacuum at about 67° C. for about 12 hours. Thereaction mixture is dissolved in hot ethyl acetate and concentrated invacuo forming a precipitate. The precipitate is filtered and thefiltrate evaporated, the residue dissolved in methylene chloride andchromatographed (silica gel: 230-400 mesh) eluting with methylenechloride and methanol. The fractions eluted with 5% MeOH/CH₂ Cl₂ werecombined and concentrated affording the desired product as an oil whichis used in the next step without further purification.

Step 2.3-Hydroxymethyl-5-[3-[5-[1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy]]propylamino]-1-methyl-1H-1,2,4-triazole.

A mixture of1-acetoxyacetyl-2-methyl-2-[phenylmethyleneamino]-3-[3-[5-(1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy)propyl]guanidine(7.5 g), aqueous hydrochloric acid (12 N, 250 ml) and absolute ethanol(30 ml) is stirred at RT for about 20 hours. The reaction mixture iswashed with ether and the aqueous layer neutralized to pH 7, treatedwith 10.3 ml of 4 M KOH, diluted with ethanol (30 ml) and stirred for 35min. The ethanol in the reaction mixture is evaporated in vacuo and theaqueous solution extracted with ethyl acetate. The organic extract isdried over MgSO₄, filtered and concentrated in vacuo forming a solid.The solid is stirred with acetonitrile, filtered and the filtered soliddissolved in hot acetonitrile. Upon cooling a precipitate forms which isfiltered, dissolved in methanol and chromatographed (silica gel, 230-400mesh). The eluted fractions were combined, concentrated andrecrystallized from acetonitrile affording the desired triazole, M.P.150°-153° C.

EXAMPLE 20

THE PREPARATION OF3-HYDROXYMETHYL-5-[3-[4-[1-PIPERIDINYLINDANYLOXY]]PROPYLAMINO]-1-METHYL-1H-1,2,4-TRIAZOLE

Step 1.1-Acetoxyacetyl-2-methyl-2-[phenylmethyleneamino]-3-[3-[4-(1-piperidinylindanyloxy)propyl]guanidine.

A neat mixture ofmethyl-N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate(6.7 g) and 4-(3-aminopropoxy)-1-piperidinylindan (6.0 g) is heated to65° C. under house vacuum for about 18 hours. Boiling ethyl acetate (70ml) is added to the heated mixture and the mixture stirred. The mixtureis allowed to cool forming a precipitate which is filtered and thefiltrate is concentrated in vacuo. The residue is triturated with etherforming a precipitate which is filtered. The filtrate is concentrated invacuo yielding the desired product as an oil which is used in the nextstep without further purification.

Step 2.3-Hydroxymethyl-5-[3-[4-[1-piperidinylindanyloxy]]propylamino]-1-methyl-1H-1,2,4-triazole.

A mixture of1-acetoxyacetyl-2-methyl-2-[phenylmethyleneamino]-3-[3-[4-(1-piperidinylindanyloxy)propyl]guanidine(11.7 g), aqueous hydrochloric acid (12N, 250 ml) and absolute ethanol(45 ml) is stirred at RT for about 20 hours. The reaction mixture iswashed with ether and the aqueous layer neutralized to pH 7, treatedwith 16 ml of 4 M KOH, diluted with ethanol (45 ml) and stirred for anadditional 1.5 hour. The reaction mixture is concentrated in vacuo andthe aqueous concentrate extracted with ethyl acetate, the extract driedover MgSO₄, filtered and concentrated in vacuo. The residue is dissolvedin methanol and chromatographed (silica gel, 230-400 mesh) eluting withmethanol. The eluted fractions are combined and concentrated in vacuo toan amber oil, which is triturated with anhydrous ether to give thedesired triazole as a white solid, M.P. 116°-119° C.

EXAMPLE 21 THE PREPARATION OF 3-(3-AMINOPROPOXY)-1-(PIPERIDINYLMETHYL)BENZOCYCLOBUTENE

Step 1. α-Cyano-4-methoxycinnamic acid.

A stirred mixture of p-anisaldehyde (60.7 ml), ammonium acetate (7.5 g),cyanoacetic acid (42.5 g), pyridone (70 ml) in toluene (390 ml) isrefluxed using a Dean Stark trap until about 9 ml of water is collected.The reaction mixture is cooled and the solid precipitate filtered andstirred with 10% aqeuous HCL. The solid is filtered and recrystallizedfrom methanol yielding the desired product.

Step 2. α-Cyano-β-(4-methoxyphenyl)propionic acid.

Sodium borohydride (30.2 g) is added portionwise over a period of 2hours to a stirred mixture of α-cyano-4-methoxycinnamic acid (52.5 g) inaqueous saturated NaHCO₃ (200 ml) and methanol (600 ml) cooled to about15° C. The reaction mixture is allowed to warm to RT, stirred at RT for30 min and concentrated in vacuo. The residue is partitioned betweenwater and ether and the aqeuous layer acidified and extracted withether. The ether extract is washed, dried over Na₂ SO₄, filtered and thefiltrate evaporated in vacuo producing a liquid which is crystallizedfrom toluene yielding the desired product as a solid, M.P. 94°-95° C.

Step 3. 4-Methoxyphenylpropionitrile.

A stirred solution of α-cyano-β(4-methoxyphenyl)propionic acid (127.3 g)in DMF (280 ml) is heated to 150° C. for 5 hours. The reaction mixtureis cooled, poured into a liter of water and extracted with ether. Theether extract is washed, dried over Na₂ SO₄, filtered and the filtrateevaporated in vacuo yielding a liquid which upon distillation yields thedecarboxylated product as a clear liquid, B.P. 115° C. (1 mm).

Step 4. 3-Bromo-4-methoxyphenylpropionitrile.

Bromine (21.4 ml) is added dropwise over a period of 1 hour to a stirredsolution of 4-methoxyphenylpropionitrile (67.5 g) and sodium acetate(68.4 g) in glacial acetic acid (420 ml). The reaction mixture isstirred for an additional 30 minutes and partitioned between water andether. The ether layer is washed with sodium carbonate solution, 10%aqueous NaOH, saturated salt, dried over Na₂ SO₄ and filtered. Thefiltrate is evaporated in vacuo yielding the desired product, B.P.155°-158° C. (4 mm).

Step 5. 1-Cyano-5-methoxybenzocyclobutene.

3-Bromo-4-methoxyphenylpropionitrile (54.28 g) is added dropwise over aperiod of about 20 minutes to a stirred suspension of sodium amide (37.1g) in liquid ammonia (250 ml) cooled to about -33° C. under nitrogen.The reaction mixture is refluxed for 3 hours after which ammoniumnitrate (54.3 g) is added slowly to the mixture. The ammonia is allowedto evaporate overnight and the residue partitioned between water andmethylene chloride. The organic fraction is washed with 5% HCl,saturated NaCl, dried over Na₂ SO₄, filtered and the filtrate evaporatedin vacuo yielding a liquid which is chromatographed (silica gel; 300 g;Hex/Ethyl Acetate 3:1) affording the desired product as a clear liquid.

Step 6. 5-Methoxybenzocyclobutene-1-carboxylic acid.

1-Cyano-5-methoxybenzocyclobutene (29 g) is stirred with saturated KOHin ethanol (180 ml) for about 12 hours under nitrogen at RT. Water (60ml) is added to the reaction mixture which is refluxed for about 3hours. The mixture is cooled to RT, diluted with water, washed withether and the aqueous layer acidified forming an oil. The oil isdissolved in ether and the ethereal solution washed, dried over Na₂ SO₄,filtered and evaporated in vacuo affording the desired product as anoil.

Step 7. 5-Methoxy-1-hydroxymethylbenzocyclobutene.

A solution of 5-methoxybenzocyclobutene-1-carboxylic acid (32.0 g) inether (1.2 l) is added dropwise to a stirred suspension of LAH (15.5 g)in ether (650 ml) under nitrogen. The reaction mixture is stirred at RTfor 4 hours, after which, water (15.5 ml), 15% NaOH (15.5 ml) and asecond portion of water added (46 ml) sequentially to the reactionmixture resulting in the formation of a precipitate. The ethereal layeris filtered, dried over Na₂ SO₄, filtered and concentrated in vacuoyielding the desired product as an oil.

Step 8. 5-Methoxy-1-hydroxymethylbenzocyclobutene mesylate.

Methane sulphonyl chloride (13.4 ml) is added dropwise to a stirredsolution of 5-methoxy-1-hydroxymethyl benzocyclobutene (26 g) andtriethylamine (26.5 ml) in methylene chloride (670 ml) cooled to 0° C.under nitrogen. The reaction mixture is allowed to warm to RT, stirredfor 2 hours at RT, washed with water and saturated salt, dried over Na₂SO₄, and filtered. The filtrate is concentrated in vacuo yielding thedesired product as a liquid.

Step 9. N-(5-Methoxy-1-piperidinylomethyl-benzocyclobutene.

A solution of 5-methyl-1-hydroxymethylbenzocyclobutene mesylate (38 g)and piperidine (45 ml) in toluene (180 ml) is refluxed under nitrogenfor about 12 hours. The reaction mixture is filtered and the filtrate isevaporated in vacuo leaving a liquid residue which is used withoutfurther purification in the next step.

Step 10. 5-Hydroxy-1-(1-piperidinylmethyl)-benzocyclobutane.

A solution of N-(5-methoxy-1-benzocyclobutenylmethyl)piperidine (0.75g), trimethylsilyliodide (0.6 ml) in chloroform (1.6 ml) is stirred forabout 18 hours under nitrogen at about 50° C.

Methanol is added to the reaction mixture resulting in the formation ofa precipitate which is filtered and the filtrate concentrated in vacuoto a red oil. The oil is partitioned between ether and saturated aqueoussodium bicarbonate. The layers are separated and the aqueous layerwashed with ether. The ether extracts are combined, washed withsaturated salt, dried over Na₂ SO₄, filtered and the filtrate evaporatedaffording the desired phenolic compound as a solid.

Step 11. 5-(3-Bromopropoxy)-1-(1-piperidinylmethyl)-Benzocyclobutene.

Potassium hydroxide (1.5 g, 10%) is added over a period of 1 hour 15 minto a stirred suspension of3-hydroxy-1-(1-piperidinylmethyl)benzocyclobutene (1.0 g), andtetrabutylammonium chloride (0.13 g) in 1,3-dibromopropane (4.6 ml) andthe resulting mixture stirred at RT under nitrogen for two days. Thereaction mixture is partitioned between ice-water and ether and theaqueous layer separated and extracted with ether. The combined organicextract is washed with water, ice cold 5% aqueous HCl thereby forming aprecipitate which is filtered and washed with ether. The acidic layer isalkalized forming an oily precipitate which is taken up in ether. Thecombined ether fractions are washed with water, dried over Na₂ SO₄,filtered and concentrated in vacuo yielding the desired product as anoil which is used in the next step without further purification.

Step 12. 5-(3-Azidopropoxy)-1-(1-piperidinylmethyl)-benzocyclobutene.

Sodium azide (0.8 g) is added to a stirred solution of5-(3-aminopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene (0.8 g) (fromStep 11 above) in ethanol/water (16 ml/1.6 ml) and the mixture heated toreflux for 24 hours. The reaction mixture is cooled and partitionedbetween water and methylene chloride. The organic layer is separated,washed with water, dried over Na₂ SO₄, filtered and concentrated invacuo, yielding the desired azido compound as an oil.

Step 13. 5-(3-Aminopropoxy)-1-(1-piperidinylmethyl)-benzocyclobutene.

A solution of the azido cyclobutene (0.7 g) (of Step 12 above) in ether(2.5 ml) is added over a period of about 30 min to a suspension of 0.15g LAH in anhydrous ether (30 ml) stirred under nitrogen. The mixture isrefluxed for about 1.5 hours and cooled. Water (0.15 ml), aqueous NaOH(15% solution, 0.15 ml) and water (0.45 ml) are added to the reactionmixture and stirring continued for about one hour. The mixture isfiltered, the solid washed with ether and the filtrate dried over Na₂SO₄. The dried ether extract is filtered, concentrated in vacuo, and theresidue is dissolved in methylene chloride, dried, filtered andconcentrated yielding the desired product as an oil.

EXAMPLE 22 The Preparation of3-(3-aminopropoxy)-1-(1-piperidinylmethylbenzocyclobutene

Step 1. 4-(3-Chloropropoxy)-1-indanone.

1-Bromo-3-chloropropane (17.3 g) is added to a stirred mixture of4-hydroxyindanone (14.8 g), potassium carbonate (15.3 g) in DMF/water(150 ml/50 ml) and the reaction mixture stirred at RT for about 4 days.The reaction mixture is partitioned between water and methylene chlorideand the organic layer is separated, dried, filtered and evaporated,affording a residue which is chromatographed on a silica gel column toyield the desired product as a white solid.

Step 2. 4-(3-Chloropropoxy)-2-oxime-1-indanone.

12.5 g of n-butyl nitrite is added to a stirred solution of4-(3-chloropropoxy)-1-indanone (17.6 g) and hydrochloric acid (12N, 39.2ml) in methoxyethanol (315 ml) and the mixture stirred at RT for 2hours. The reaction mixture is poured into water, cooled to 0° C. in anice bath resulting in the formation of a precipitate which is filtered,washed with water and dried yielding the desired oxime product as ayellow crystalline solid.

Step 3. 3-(Chloropropoxy)-2-diazo-1-indanone.

Ammonium hydroxide (8.74 ml, 15N) is added to a stirred mixture of4-(3-chloropropoxy)-2-oxime-1-indanone (16.6 g) and sodium hydroxide(2.6 g) in water (500 ml) at 2° C. Sodium hypochlorite (218 ml, 5.25%aqueous solution) is added slowly to the reaction mixture maintained atabout 2° C. and allowed to stand at RT for about 4 hours. The reactionmixture is filtered and the solid washed with water. The solid isdissolved in methylene chloride, filtered, dried over Na₂ SO₄, andevaporated in vacuo resulting in the desired product as a solid.

Step 4. 3-(3-Chloropropoxy)benzocyclobutene-1-carboxylic acid.

A solution of 3-(chloropropoxy)-2-diazo-1-indanone (11.4 g) and sodiumbicarbonate (9.4 g) in a solvent mixture of THF (800 ml) and water (140ml) is photolyzed for 63 hours. The THF is evaporated in vacuo and theaqueous remainder partitioned between water and methylene chloride. Theaqueous layer is acidified with conc. HCl and extracted with methylenechloride. The methylene chloride extract is washed with saturated NaCl,dried over Na₂ SO₄, filtered and concentrated in vacuo yielding thedesired carboxylic acid as an oil.

Step 5. 3-(3-Chloropropoxy)-1-hydroxymethylbenzocyclobutene.

A solution of 3-(3-chloropropoxy)benzocyclobutene-1-carboxylic acid (2.6g) in THF (25 ml) is added to a stirred suspension of LAH (0.9 g) in 40ml of ether under nitrogen. The reaction mixture is stirred at RT for 4hours, and quenched with water (0.9 ml), 15% NaOH solution (0.9 ml) andwater (2.6 ml). The reaction mixture is filtered and the ether/THFevaporated in vacuo. The residue is extracted with methylene chloride,the organic extract dried over Na₂ SO₄, filtered and the solventevaporated in vacuo yielding the desired product as an oil.

Step 6. 3-(3-Chloropropoxy)-1-hydroxymethylbenzocyclobutene mesylate.

Methane sulfonylchloride (1.13 g) is added dropwise to a stirredsolution of 3-(3-chloropropoxy)-1-hydroxymethylbenzocyclobutene (1.83 g)and triethylamine (1.58 ml) in methylene chloride (32 ml) at 5° C. undernitrogen. The reaction mixture is stirred at RT for about 2 hours,washed with water, saturated NaCl, dried over Na₂ SO₄, filtered andevaporated in vacuo yielding the desired product as an oil.

Step 7. 3-(3-Chloropropoxy)-1-(1-piperidinylmethyl)benzocyclobutene.

Piperidine (3.19 ml) is added to a solution of3-(3-chloropropoxy)-1-hydroxymethylbenzocyclobutene mesylate (2.45 g) intoluene (32 ml) and the reaction mixture refluxed under nitrogen forabout 12 hours. The reaction mixture is diluted with ethyl acetate andextracted with saturated NaHCO₃ followed by saturated NaCl. The organicextract is dried, filtered and concentrated yielding the crude productused in the next step.

Step 8. 3-(3-Azidopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene.

Sodium iodide (3 g) is added to a stirred solution of3-(3-chloropropoxy)-1-(1-piperidinylmethyl)benzocyclobutene (0.87 g) in12 ml of DMF. The reaction mixture is stirred under nitrogen for 12hours, sodium azide (1.17 g) is added to this solution followed by water(1.2 ml). The resulting suspension is heated at 75° C. for 5 hours. Thereaction mixture is partitioned between water and methylene chloride andthe organic layer is separated, washed, dried, filtered and evaporatedin vacuo yielding the azide product as an oil.

Step 9. 3-(3-Aminopropoxy)-1-(1-piperidinylmethyl)benzocyclobutene.

A solution of the azido benzocyclobutenylmethyl compound (0.8 g) (step 8above) in THF (5.2 ml) is added over a period of 30 min to a suspensionof LAH (0.125 g) in anhydrous ether (16.5 ml) stirred under nitrogen.The mixture is refluxed for about 2 hours and cooled. Water (0.125 ml),aqueous NaOH (15% solution, 0.125 ml) and water (3.75 ml) are added tothe cooled mixture which is filtered. The solid is washed with ether andthe filtrate dried over Na₂ SO₄. The dried filtrate is filtered,evaporated in vacuo and chromatographed (silica gel) eluting with 1:1ethyl acetate/MeOH. The pure fractions are combined and evaporated invacuo yielding an oil. NMR analysis identifies the oil as the desiredproduct.

EXAMPLE 23 The Preparation of3-amino-5-[3-[3'-[[1-piperidinylmethyl]benzocyclobutenylyoxy]propylamino]]-1-methyl-1H-1,2,4-triazole

3-[3-Aminopropoxy]-1-piperidinylmethylbenzocyclobutene (1.5 g) andN-cyano-1-methyl-2-phenylmethylenehydrazinecarboximidethioic acid methylester are dissolved in CH₂ Cl₂ and evaporated in vacuo. The neat mixtureis heated to 70° C. for four hours and the resultant glass is dissolvedin 5% aqueous HCl (30 ml)/acetone (20 ml) and washed with ether. Theaqueous solution is made alkaline resulting in a yellow oil which istaken up in ethyl acetate, washed with saturated salt, dried over Na₂SO₄, filtered and evaporated in vacuo to a yellow oil which ischromatographed (silica gel, 1/1:MeOH/EtOAc). The purified fractions arecombined and evaporated to a glass which is triturated with etheryielding the desired product as a solid, M.P.=114°-116° C.

EXAMPLE 24 The Preparation of5-(3-aminopropoxy)-1-piperidinylmethyl-1,2,3,4-tetrahydronaphthalene

Step 1. 5-Methoxy-Spiro(1,2,3,4-tetrahydronaphthalene)-1,2'-oxirane.

Dimethylsulfoxide (500 ml) is added over a period of 15 minutes to astirred mixture of sodium hydride (22.4 g) (60% dispersion oil removedby pet. ether) and trimethylsulfoxonium iodide (116 g) under nitrogen.The reaction mixture is stirred at RT for 1 hour. A solution of5-methoxytetralone (75 g) in DMSO (350 ml) is added over a period of 15min to the reaction mixture and stirred at RT for 2 hours, at 50°-55° C.for an additional hour and poured into water/crushed ice. The aqueousmixture is extracted with ether and the ether extract washed, dried overNa₂ SO₄, filtered and the filtrate evaporated in vacuo yielding thedesired product as an oil.

Step 2.1-Hydroxy-5-methoxy-1-piperidinylmethyl-1,2,3,4-tetrahydronaphthalene.

A solution of 5-methoxy-spiro(1,2,3,4-tetrahydronaphthalene)-1,2'-oxirane (73 g) and piperidine (49g, distilled) in absolute ethanol (750 ml) is refluxed under nitrogenfor 18 hours. The reaction mixture is evaporated in vacuo and theresidue partitioned between ether and 5% aq. HCl. The acidic layer isseparated and washed with ether, made strongly alkaline and theprecipitated oil extracted with ether. The ethereal extract is washed,dried, filtered and the filtrate evaporated in vacuo yielding thedesired product as an oil.

Step 3. 5-Methoxy-1-piperidinylmethyl-1,2-dihydronaphthalene.

The hydroxy compound of Step 2 (75 g) is dissolved in 20% (w/w) sulfuricacid (375 ml) and refluxed under nitrogen for 18 hours. The cooledmixture is poured into ice-water, extracted with ether and the aqueouslayer made strongly alkaline. The precipitated oil is extracted intoether which is washed, dried, filtered and evaporated in vacuo yieldingthe desired product as an oil.

Step 4. 5-Methoxy-1-piperidinylmethyl-1,2,3,4-tetrahydronaphthalene.

5% Palladium on carbon (3.0 g) is added to a solution of5-methoxy-1-piperidinylmethyl-1,2-dihydronaphthalene (63 g) in absoluteethanol (600 ml) and placed under H₂ at an initial pressure of 47 psifor 30 min. The reaction mixture is filtered and the filtrate evaporatedin vacuo yielding the desired product as an oil.

Step 5. 5-Hydroxy-1-piperidinylmethyl-1,2,3,4-tetrahydronaphthalene.

A solution of the 5-methoxy compound from step 4 above (41 g), 47-49%hydrobromic acid (410 ml) in glacial acetic acid (410 ml) is stirred atreflux under nitrogen for 2.5 hours. The cooled reaction mixture ispoured into ice/water, made alkaline and the pH adjusted until no morecloudiness appears. The resulting oil is extracted into ether, washed,dried, filtered and the filtrate evaporated in vacuo forming a solidresidue which is recrystallized from hot acetonitrile yielding thedesired product as a crystalline solid, M.P.=129°-131° C.

Step 6.5-(N-phthalimidopropoxy)-1-piperidinylmethyl-1,2,3,4-tetrahydronaphthalene

Potassium t-butoxide (13.5 g) is added to a cooled solution of thephenol from Step 5 (27 g) in DMF (250 ml) and the mixture stirred for 5min. N-(3-bromopropyl)pthalimide (58 g) is added to the stirred mixtureand stirring continued at RT for 20 hours. The reaction mixture ispartitioned between 2% NaOH solution and ethyl acetate. The ethylacetate extract is stirred with 5% aqueous HCl forming a solid. Thesolid is filtered and the aqueous layer combined with the solid and madestrongly alkaline. The resulting oil is extracted with ethyl acetate andthe extract washed, dried, filtered and evaporated in vacuo to an oilwhich is dissolved in isopropanol forming a precipitate. The precipitateis filtered, dried and recrystallized from isopropanol yielding thedesired product as a crystalline solid, M.P.=76°-77.5° C.

Step 7.5-(3-aminopropoxy)-1-piperidinylmethyl-1,2,3,4-tetrahydronaphthalene.

Hydrazine monohydrate (3.5 ml) is added to a stirred suspension of theN-pthalimido compound (25.7 g) in absolute ethanol (250 ml) and refluxedfor three hours. The mixture is stirred at RT for one hour, filtered andthe filtrate evaporated in vacuo. The residue and solid precipitate arecombined and stirred with ice cold 5% HCl for 30 min. The suspension isfiltered and the aqueous filtrate made strongly alkaline. The alkalinesolution is extracted with ether and the extract dried, filtered and thefiltrate evaporated in vacuo yielding the desired product as an oil.

The following compounds are prepared from the amino propoxy compound ofStep 7 above utilizing reaction conditions analagous to those describedin the foregoing examples.

3-Amino-5-[3-[5-(1-piperidinylmethyl-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole;M.P.=147°-8° C.

1-Cyano-2-methyl-3-[3-[5-(1-piperidinylmethyl)-1,2,3,4-tetrahydronaphthyloxy)]propyl]pseudothiourea;M.P.=111°-113° C.

1-Amino-2-[3-[5-(1-piperidinylmethyl-1,2,3,4-tetrahydronaphthyloxy)]propylamino]cyclobutene-3,4-dione;M.P.=241°-245° C. (dec).

EXAMPLE 25 Resolution of Enantiomers

Step 1. Resolution of S(+) and R(-) isomers of5-methoxy-1-piperidinyl-1,2,3,4-tetrahydronapthalene.

Resolution of the racemic mixture of (+)5-methoxy-1-piperidinyl-1,2,3,4-tetrahydronapthalene is accomplished byforming the diastereomeric salts thereof utilizing(+)-Dibenzoyl-D-tartaric acid and (-)-Dibenzoyl-L-tartaric acid. 95%EtOH is used as the recrystallization solvent. The melting points andspecific rotations for the resolved diastereomeric salts are listedbelow.

(A) Salt of (-)5-methoxy-1-piperidinyl-1,2,3,4-tetrahydronapthalene.

M.P=151.5°-152° C.

[α]_(D) ^(RT) =-92.41°

(conc.=1 g/100 ml MeOH)

(B) Salt of (+)5-methoxy-1-piperidinyl-1,2,3,4-tetrahydronapthalene.

M.P.=153°-153.5° C.

[α]_(D) ^(RT) =+94.68°

(conc.=1 g/100 ml)

The free bases are oils and have the following specific rotations:

from (A) above

[α]_(D) ^(RT) =-103.52° (conc.=1.5 g/100 ml CH₂ Cl₂)

from (B) above

[α]_(D) ^(RT) =+102.26°.

The following enantiomers are prepared from the optically active5-methoxy starting materials by the methods described herein above.

    ______________________________________                 M.P.   [α].sub.D.sup.RT                                 (CH.sub.2 Cl.sub.2)    ______________________________________    R(-)-5-hydroxy-1-piperi- dinyl-1,2,3,4-tetrahydro- napthalene                   145°- 146.5° C.                            -113.51°                                      ##STR265##    R(-)-5-(3-phthalimidopro- poxy)-1-piperidinyl-1,2,3,4- tetrahydronapthalen    e              63°- 65° C.                            -43.02°                                      ##STR266##    R(-)-5-(3-aminopropoxy)- 1-piperidinyl-1,2,3,4-tetra- hydronapthlane                            -69.13°                                      ##STR267##    R(-)-1-cyano-2-methyl-3-[3- [5-[1-piperidinyl-1,2,3,4- tetrahydronapthylox    y]- propyl]pseudothiourea                   123°- 124° C.                            -56.54°                                      ##STR268##    R(-)-3-amino-5-[3-[5-(1- piperidinyl-1,2,3,4-tetra- hydronapthyloxy)]propy    l- amino]-1-methyl-1H 1,2, 4-triazole                   155- 157° C.                            -57.09°                                      ##STR269##    S(+)-5-hydroxy-1-piperi- dinyl-1,2,3,4-tetrahydro- napthalene                   144.5°- 146° C.                            +115.82°                                      ##STR270##    S(+)-5-(3-phthalimidopro- poxy)-1-piperidinyl-1,2,3,4- tetrahydronapthalen    e              82- 83.5° C.                            +49.95°                                      ##STR271##    S(+)-5-(3-aminopropoxy)- 1-piperidinyl-1,2,3,4-tetra- hydronapthlane                   --       +80.26°                                      ##STR272##    S(+)-1-cyano-2-methyl-3-[3- [5-[1-piperidinyl-1,2,3,4- tetrahydronapthylox    y]]- propyl]pseudothiourea                   123.5- 124.5° C.                            +56.48°                                      ##STR273##    S(+)-3-amino-5-[ 3-[5-(1- piperidinyl-1,2,3,4-tetra- hydronapthyloxy)]prop    yl- amino]-1-methyl-1H1,2, 4-triazole                   155- 157° C.                            +56.00°                                      ##STR274##    ______________________________________

Various tests in animals have been carried out to show the ability ofthe compounds of this invention to exhibit pharmacological responsesthat can be correlated with activity in humans. These tests involve suchfactors as the effect of the compounds of Formula I on gastric secretionand their H₂ antagonist and cytoprotective activity. It has been foundthat the compounds of this invention when tested in the above variety ofsituations show a marked activity.

One such test is the gastric secretion test. This test is carried out asfollows: Shay rats are fasted for 4-8 hours, and water is given ad lib.The rats are selected at random and separated into groups of 10. Theanimals are treated intraduodenally (I.D.) with the test compounds orthe vehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at 4 hourspost-drug administration, the stomach removed and its contents assayedfor volume, pH and total acids.

A second gastric secretion test is carried out on the dog. This isoutlined in the Handbook of Physiology, Section 6: Alimentary Canal,Volume II: Secretion. American Physiology Society, Washington, D.C.,1967.

It has been found that the compounds of this invention, when subjectedto the above gastric secretion tests, display marked ability to decreasegastric volume and gastric acidity. These tests are known to correlatewell with gastric activity in humans and are standard tests used todetermine anti-secretory properties.

The compounds of Formula I have been found to be histamine H₂ -receptorantagonists by the results obtained in the following H₂ -antagonisttests.

A. Isolated Guinea Pig Atria

The H₂ -receptor antagonist activity of the compounds of Formula I ismeasured by observing the beat rate response versus compoundconcentration in isolated guinea pig atria. A discussion of criteria toevaluate these dose-response curves may be found in, E. J. Ariens, G. A.J. vanOs, A. M. Simonis, and T. M. van Rossum, "A Molecular Approach toGeneral Pharmacology", Sections 11A, 11B, and 111, MolecularPharmacology: The Mode of Action of Biologically Active Compound. Vol.1, Academic Press (1964).

1. Tissue Bath

A fifty ml jacketed tissue bath is maintained at 30° C. The bathconsists of a Krebs-Henseleit buffer aerated with 95% O₂ -5% CO₂, (pH7.4). The buffer is prepared by mixing: 4 ml of an aqueous (distilleddeionized) solution of CaCl₂.2H₂ O (0.37 g/ml); 4 ml of an aqueous(distilled deionized) solution of MgSO₄.7H₂ O (0.29 g/ml); 7.2 g ofglucose; and, 2 liters of aqueous (distilled deionized) solutioncontaining NaCl (28 g), NaHCO₂ (8.4 g), KCl (1.4 g) and KH₂ PO₄ (0.6 g).

2. Preparation of Atria

Male albino guinea pigs (400-700 g, preferably 500-600 g) are killed bya blow to the back of the head and exsanguinated by cutting jugularveins and carotid arteries. The thoracic skin is opened from this neckcut and the rib cage exposed. Both sides of the rib cage and thediaphragm are cut and laid back, exposing the heart. The heart isremoved by cutting through the vessels above and behind it while it isslightly elevated with forceps holding the ventricle tip. The heart isimmediately placed in warm, aerated buffer and further dissected in alarge petri dish of the same buffer. Since the pericardium is removed,it is possible to slip iris scissors between the atria and ventricleswhile holding the aorta and vessels with tweezers and cut off the atria.The atria are then dissected from any remaining tissue and vessels andsuspended in the bath using small, curved taper-point needles formedinto hooks and tied to an S-shaped hook and the L-shaped lower supportwith 00 silk.

A Beckman Type 9308 Strain Gauge Coupler connects a Beckmancardiotachometer to a Grass FT03C strain gauge supported in a rack andpinion clamp. The upper hook of the strain gauge is placed in the edgeof the left atrium and the lower hook in the tip of the right atrium.The lower support is clamped in a femur clamp and the upper hook issuspended from the strain gauge lug. The strain gauge is raised untilthe resting tension on the tissue is 1 gram. The tissue is allowed tostabilize for about one hour with several buffer washings and tensionadjustments before the addition of the test compounds.

3. Test Procedure

A control dose-response curve using cumulative, approximately triplingdoses is obtained in all three running from 0.1 to 30.0M histamine (0.1,0.3, 1.0, 3.0, etc.) In order to minimize volume changes when addingdrugs to the bath, small volumes of concentrated solutions are used. Itis convenient to make up a 0.5M solution and dilute it to give 50, 5 and0.5 mM solutions.

Data recorded consists of the initial baseline rate and the stableplateau rate after each addition. Histamine is then washed out and thetissues are allowed to stabilize again near the initial baseline rate;this may take several rinses and 1 hr. The test compound is then addedat the same cumulative doses and rates again recorded. If the compoundbehaves as an agonist and stimulates, then the dose is increased untilthe rate plateaus or the concentration is 1.0 mM. If, however, noagonistic activity is observed when the concentrations has reached 100Mthen its antagonistic activity is assessed by repeating the histaminecurve without washing out the test compound. Reversibility of effect isassessed by attempting to wash out the test compound and/or histamineand repeat the histamine curve. Erratic or irregular beating or anyother abnormal behavior at any time is noted. Calculations consist ofthe change in rate from base line and that change as a percentage of themaximum rate obtained in the initial control curve. The mean of thosepercentages (+SEM) is plotted as a function of agonist concentration(either histamine or test compound) to evaluate the type of response.

B. Lumen Perfused Rat Stomach--Effect on the Gastric Secretion

Male Sprague-Dawley rats weighing between 350 and 500 gm are housedindividually according to standard animal husbandry procedures and aredeprived of food twenty-four hours prior to testing. The rats areanesthetized by an intraperitoneal injection of 25% solution of urethane(0.5 to 0.7 ml/100 g of body weight). Once anesthetized, the trachea isexposed and cannulated with PE 100 tubing. The jugular vein is exposedand cannulated with PE 50 tubing bevelled at the tip. The abdomen isopened through a midline incision, and the esophagus is isolatedexcluding the vagus nerve. PE 190 tubing, with a flange on one end, ispassed down the rat's mouth through the esophagus and into the stomach.The esophagus is tied off and the tubing checked to make sure that it issecurely in the stomach. The duodenum is then identified and a small cutmade about 1 cm below the pyloric sphincter. A piece of PE 320 tubing(flanged at one end) is inserted through the cut and into the stomach.It is secured firmly by tying a ligature around the pylorus. Using a 50ml syringe, the stomach is flushed out with 0.4 mM NaOH through theesophageal tube until the perfusate emerging from the pyloric tube isclear. The animal is placed on a tilted table covered with a Gordon-Ruppwater blanket Model `K` to maintain the rat's body temperature at 30° C.The tube going into the esophagus is attached to a Sage Peristaltic Pumpand 0.4 mN NaOH (pH 10.0) is perfused and collected in 30 ml beakers.The beakers are changed every 10 or 15 minutes and the pH of thesesamples are recorded. Once the pH has stabilized around 6.5-7.5, drugsthat affect gastric secretion are given intravenously. The effectivenessof a compound is based on its ability to prevent a drop in pH initiatedby a gastric stimulant, such as histamine. See, Ghosh, M. N. and Schild,H. O., Brit. J. Pharmacol., 13: 54 (1958).

Compounds within the scope of Formula I have also been determined toexhibit anti-ulcer activity. The anti-ulcer properties of thesecompounds can be evaluated using an anti-ulcer assay in which aspirin oranother nonsteroidal anti-inflammatory agent is used to induce gastriculcers in the rat according to the following test procedure.

See, Corell, T., "Interaction of Salicylates and other Non-steroidalAnti-inflammatory Agents in Rats as Shown by Gastro-ulcerogenic andAnti-inflammatory Activities, and Plasma Concentrations", Acta.Pharmacology et. Toxicology, 45, 225-231 (1979).

Male Sprague-Dawley rats 140-170 g are housed according to standardanimal husbandry procedures. The rats are fasted twenty-four hours priorto testing. On the test day, rats are divided into groups of 5 or 10,with one group serving as controls and receiving vehicle (for example,distilled water or a 0.1% Tween 80 solution). The test compounds, usinglogarithmic doses, are administered at a dose volume of 10 ml/kg. Thirtyminutes post-drug, the rats are orally administered (10 ml/kg) aspirinor indomethacin suspended in 0.1% Tween 80 at a dose of 150.0 or 20.0mg/kg, respectively. Four hours following indomethacin administration(five hours after aspirin administration) animals are sacrificed viacervical dislocation; their stomachs are removed, opened along thegreater curvature, and gently rinsed and examined for lesions with a10×magnifying glass; the following scale is employed:

    ______________________________________    Grade         Description    ______________________________________    0             No lesions    1             5 lesions, all <2 mm    2             5 lesions, at least 1 > 2 mm    3             5-10 lesions, all <2 mm    4             5-10 lesions, at least 1 > 2 mm    5             10 lesions, all <2 mm    6             10 lesions, at least 1 > 2 mm    7             Perforation    ______________________________________

The average ulcer severity (±S.E.) for each group of animals iscalculated. The percent inhibition for each test compound is calculatedas follows: ##EQU1##

The compounds of Formula I have also been determined to exhibitcytoprotective activity.

The cytoprotective effectiveness of the compounds of Formula I isevaluated according to the following test procedure.

Male Sprague-Dawley rats 150-200 g are housed according to standardanimal husbandry procedures. The rats are fasted twenty-four hours priorto testing. On the test day, rats are divided into groups of 6, with onegroup serving as controls and receiving vehicle (for example, distilledwater or a 0.5% Methocel solution). The test compounds, usinglogarithmically spaced doses, are administered at a dose volume of 5ml/kg. Ten minutes post-drug, the rats are orally administered 1 ml ofabsolute alcohol, 0.2N NaOH (1 ml) or 0.6N HCl (1 ml), regardless ofbody weight. One hour after administration animals are sacrificed bycervical dislocation, their stomachs are removed, opened along thegreater curvature, rinsed under running tap water and examined forlesions with a 2×-10× magnifying glass.

The reduction of lesion count, lesion severity score and ulcer index ascompared to similar measurements made in the controls was expressed as apercentage. Measurement of statistical significance of the results wasdone by standard methods.

The average ulcer severity (±S.E.) for each group of animals iscalculated. The percent inhibition for each test compound is calculatedas follows: ##EQU2##

The results of the anti-secretory, anti-ulcer and cytoprotective assays,detailed above, establish the anti-secretory activity, the H₂ -receptorantagonist activity, the anti-ulcer activity, the cytoprotectiveactivity, and the utility of the compounds of the present invention inthe treatment of peptic ulcers in mammals, including humans. Thesecompounds both aid in the healing of such ulcers and also prevent theirformation.

The most preferred anti-secretory and anti-ulcer compound within thescope of Formula I is3-amino-5-[3-[4-[1-(1-piperidinyl)indanyloxy]]propylamino]-1-methyl-1H-1,2,4-triazoleand the pharmaceutically acceptable salts thereof.

Another preferred compound is3-amino-5-[3-[5-[1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthyloxy]]propylamino]-1-methyl-1H-1,2,4-triazoleand the pharmaceutically acceptable salts thereof.

The most preferred class of compound according to the present inventioncomprises an optically active isomeric class of compound according toFormula I, wherein the tetrahedral carbon atom in the 1-position is inthe S configuration.

It has been found that the S(+) enantiomer of a compound of Formula Ipossesses greater histamine H₂ -receptor antagonist activity than itsR(-) isomer. This increased activity is exemplified byS(+)-3-amino-5-[3-[5-(1-piperidinyl-1,2,3,4-tetrahydronaphthyloxy)]propylamino]-1-methyl-1H-1,2,4-triazole, the H₂ -antagonist activity ofwhich is about ten times that of its R(-) isomer. The separation ofactivity may be measured in the pharmacological tests described hereinabove including: the guinea pig atria test; the lumen perfused stomachtest; the aspirin induced ulcer test; and the pylorus-ligated rat test.

In particular, the compounds according to Formulae I to VI are useful:in the treatment and prevention of hyperacidity and gastrointestinalulceration; for decreasing gastrointestinal acid secretion in mammals;and for enhancing the gastrointestinal resistance to gastrointestinalirritants in humans and other mammals.

For all these purposes, the compounds of this invention can be normallyadministered orally or parenterally. Oral administration is preferred.

The compounds according to the invention, preferably in the form of asalt, may be formulated for administration in any convenient way, andthe invention includes within its scope pharmaceutical compositionscontaining at least one compound according to the invention adapted foruse in human or veterinary medicine. Such compositions may be formulatedin a conventional manner using one or more pharmaceutically acceptablecarriers or excipients. Such compositions may also contain if requiredother active ingredients, for example, H₁ -antagonists, or knownantacids such as aluminum hydroxide, magnesium hydroxide, magnesiumtrisilicate, aluminum glycinate, or calcium carbonate. Suitable carriersinclude diluents or fillers, sterile aqueous media and various non-toxicorganic solvents. The compositions may be formulated in the form oftablets, capsules, lozenges, troches, hard candies, powders, aqueoussuspensions, or solutions, injectable solutions, elixirs, syrups and thelike and may contain one or more agents selected from the groupincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a pharmaceutically acceptablepreparation.

The particular carrier and the ratio of active compound to carrier aredetermined by the solubility and chemical properties of the compounds,the particular mode of administration and standard pharmaceuticalpractice. For example, excipients such as lactose, sodium citrate,calcium carbonate and dicalcium phosphate and various disintegrants suchas starch, alginic acid and certain complex silicates, together withlubricating agents such as magnesium stearate, sodium lauryl sulphateand talc, can be used in producing tablets. For a capsule form, lactoseand high molecular weight polyethylene glycols are among the preferredpharmaceutically acceptable carriers. Where aqueous suspensions for oraluse are formulated, the carrier can be emulsifying or suspending agents.Diluents such as ethanol, propylene glycol, glycerin and chloroform andtheir combinations can be employed as well as other materials.

For parenteral administration, solutions or suspensions of thesecompounds in sesame or peanut oil or aqueous propylene glycol solutions,as well as sterile aqueous solutions of the soluble pharmaceuticallyacceptable salts described herein can be employed. Solutions of thesalts of these compounds are especially suited for intramuscular andsubcutaneous injection purposes. The aqueous solutions, including thoseof the salts dissolved in pure distilled water, are also useful forintravenous injection purposes, provided that their pH is properlyadjusted, suitably buffered, and made isotonic with sufficient saline orglucose.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of gastrointestinal disease conditions or symptoms, such asduodenal and peptic ulcer. In general, the dose can be between about 0.1mg/kg and 100 mg/kg (preferably in the range of 1 to 20 mg/kg), bearingin mind, of course, that in selecting the appropriate dosage in anyspecific case, consideration must be given to the patient's weight,general health, age, and other factors which may influence response tothe drug. The daily dose can range from 1 to 4 times a day.

We claim:
 1. A compound of the formula: ##STR275## wherein: a is 0, 1 or2;b is 0 or 1; c is 1-b, 2-b or 3-b d is 0 or 1; e is 2, 3 or 4; X isoxygen, sulfur, ##STR276## Z is --NHR₄ ; R₁ is --NR₂ R₃ ; R₂ and R₃ areeach independently H or alkyl, or both together with the nitrogen towhich they are attached form a 5, 6 or 7-membered ring which may includeone to three additional hetero atoms of N, O or S; R₄ is ##STR277## R₅is H or lower alkyl; R₇ is hydrogen, lower alkyl, lower alkenyl, aryl,arloweralkyl, hydroxyloweralkyl, acyloxyloweralkyl,loweralkoxyloweralkyl, aryloxyalkyl, aroyloxyalkyl, aralkyloxyalkyl,aminoalky, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, alkoxy,alkylthio or halogen or NR₈ R₉ ; R₈ is hydrogen, loweralkyl,, loweralkenyl or arloweralkyl; R₉ is hydrogen, COR₁₀, SO₂ R₁₁ or ##STR278##R₁₀ is hydrogen, loweralkyl, aryl, arloweralkyl, loweralkoxy,heteroaryl, or monocyclic heteroarylalkyl; R₁₁ is lower alkyl or aryl;R₁₂ is hydrogen, lower alkyl, cycloloweralkyl, aryl or arloweralkyl;wherein any aryl is phenyl or substituted phenyl and any aroyl isbenzoyl;or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 wherein:a is 0; b is 0; d is 0; e is 3; and X isoxygen.
 3. A compound of the formula ##STR279## wherein: a is 0, 1 or2;c is 1, 2 or 3; d is 0 or 1; e is 2, 3 or 4; X is oxygen or sulfur; Zis --NHR₄ ; R₁ is --NR₂ R₃ ; R₂ and R₃ are each independently H oralkyl, or both together with the nitrogen to which they are attachedform a 5, 6 or 7-membered ring which may include one to three additionalhetero atoms of N, O or S; R₄ is ##STR280## R₅ is H or lower alkyl; or apharmaceutically acceptable salt thereof.
 4. A compound of the formula##STR281## wherein: a is 0, 1 or 2;c is 1, 2 or 3; d is 0 or 1; e is 2,3 or 4; X is oxygen or sulfur; Z is --NHR₄ ; R₁ is --NR₂ R₃ ; R₂ and R₃are each independently H or alkyl, or both together with the nitrogen towhich they are attached form a 5, 6 or 7-membered ring which may includeone to three additional hetero atoms of N, O or S; R₄ is ##STR282## R₅is H or lower alkyl; or a pharmaceutically acceptable salt thereof.
 5. Acompound of the formula ##STR283## wherein: a is 0, 1 or 2;d is 0 or 1;e is 2, 3 or 4; X is oxygen or sulfur; Z is --NHR₄ ; R₁ is --NR₂ R₃ ; R₂and R₃ are each independently H or alkyl, or both together with thenitrogen to which they are attached form a 5, 6 or 7-membered ring whichmay include one to three additional hetero atoms of N, O or S; R₄ is##STR284## R₅ is H or lower alkyl; or a pharmaceutically acceptable saltthereof.
 6. A compound of the formula ##STR285## wherein: a is 0, 1 or2;d is 0 or 1; e is 2, 3 or 4; X is oxygen or sulfur; Z is --NHR₄ ; R₁is --NR₂ R₃ ; R₂ and R₃ are each independently H or alkyl, or bothtogether with the nitrogen to which they are attached form a 5, 6 or7-membered ring which may include one to three additional hetero atomsof N, O or S; R₄ is ##STR286## R₅ is H or lower alkyl; or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 5 wherein:a and d are 0; e is 3; and X is oxygen.
 8. A compoundaccording to claim 5 wherein:a is 0; d is 1; e is 2; and X is sulfur. 9.A compound according to claim 5, which is3-Amino-5-[4-[5-[1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthyloxy]]butylamino]-1-methyl-1H-1,2,4-triazole or a pharmaceutically acceptablesalt thereof.
 10. A compound according to claim 5, which is3-Amino-5-[3-[5-[1-(1-piperidinylmethyl)-1,2,3,4-tetrahydronaphthyloxy)]]propylamino]-1-methyl-1H-1,2,4-triazole or a pharmaceutically acceptablesalt thereof.
 11. A compound according to claim 6, which is3-hydroxymethyl-5-[3-[4-[1-(1-piperidinyl)indanyloxy]]-propylamino]-1-methyl-1H-1,2,4-triazoleor a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 6, which is3-hydroxymethyl-5-[3-[5-[1-(1-piperidinyl)-1,2,3,4-tetrahydronaphthyloxy]]propylamino]-1,2,4-triazoleor a pharmaceutically acceptable salt thereof.
 13. A compound accordingto claim 1, wherein the carbon atom to which the R₁ --(CH₂)_(a) -groupis attached is in the S configuration.
 14. A compound according to claim5, which is the S(+) enantiomeric base or a pharmaceutically acceptablesalt thereof.
 15. A compound according to claim 6, which is the S(+)enantiomeric base or a pharmaceutically acceptable salt thereof.
 16. Acompound according to claim 1, wherein the carbon atom to which the R₁--(CH₂)_(a) - group is attached is in the R-- configuration.
 17. Acompound according to claim 1, which is the racemic mixture of the baseor a pharmaceutically acceptable salt thereof.
 18. A method fordecreasing acid secretion in the gastrointestinal tract of mammals byadministering thereto an anti-secretory effective amount of a compoundaccording to claim
 1. 19. A method for the treatment of gastrointestinalhyperacidity and ulceration in a mammal comprising administering theretoan effective amount of a compound according to claim
 1. 20. A method forenhancing the gastrointestinal resistance to gastrointestinal irritantsin humans and mammals comprising administering thereto an effectivecytoprotective amount of a compound of the formula according to claim 1.21. A pharmaceutical composition wherein the active ingredient is acompound according to claim 1 in admixture with a pharmaceuticalcarrier.